Acamprosate formulations, methods of using the same, and combinations comprising the same

ABSTRACT

Embodiments disclosed herein generally relate to acamprosate formulations, methods of use of the formulations, to methods of using the formulations optionally in combination with at least one other medication, and to combination products and compositions comprising acamprosate and at least one other medication, such as neuroleptic (antipsychotic) and/or antidepressant drugs.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/831,587, filed on Jun. 5, 2013, which isincorporated herein by reference in its entirety.

BACKGROUND

Acamprosate calcium (also referred to simply as “acamprosate”), thecalcium salt of N-acetylhomotaurine, has been marketed for over 25 yearsas a treatment for alcoholism; specifically, it has been used to treatcraving for alcohol in currently abstinent alcohol abusers. For thisindication it has had limited effectiveness. Yahn S L, Watterson L R,Olive M F: Safety and efficacy of acamprosate for the treatment ofalcohol dependence. Substance Abuse 7:1-12, 2013; Witkiewitz K, SavilleK, Hamreus K: Acamprosate for treatment of alcohol dependence:mechanisms, efficacy, and clinical utility. Therapeutics and ClinicalRisk Management 8: 45-53, 2012. Despite a number of positive clinicaltrials, and a few negative ones, the effectiveness of the drug in actualclinical use has been relatively low. In the United States, sales of thedrug have been so low that its manufacturer has stopped activelymarketing it.

While the effectiveness of acamprosate calcium for alcoholism has beendisappointing, 25 years of use in many countries, with over one millionpatients, has established that the drug is extraordinarily safe for acentral nervous system (CNS) drug. Virtually no severe adverse eventsunequivocally attributable to the drug have been reported.

Acamprosate is remarkable not only for its safety but for its mechanismof action, which is unique among CNS drugs currently approved in theUnited States. It modulates glutamate and GABA transmission, diminishingthe former when it is excessive and increasing the latter when it islow, but not interfering meaningfully with normal neural traffic. Itdoes this by indirect actions including the induction of proteinsynthesis within cells with glutamate receptors; it does not directlybind to primary glutamate or GABA receptors sites nor is it anallosteric modulator of those sites.

Because of its actions on glutamate and GABA transmission acamprosatecan correct an imbalance of excitatory (glutamate-mediated) andinhibitory (GABA-mediated) neurotransmission. Such imbalances arccurrently thought to play a role in causing or influencing the severityof diverse neurological and psychiatric conditions including tardivedyskinesia (TD), levodopa-induced dyskinesia (LID), Tourette Syndrome(TS), obsessive-compulsive disorder (OCD), posttraumatic stress disorder(PTSD), tinnitus, autism, generalized anxiety, depression, andaddictions to alcohol, nicotine, and cocaine. Several U.S. patents(e.g., U.S. Pat. Nos. 6,057,373, 6,294,583, 6,391,922, 6,689,816, and7,498,361; each of which is incorporated herein by reference in itsentirety) describe the use of acamprosate to treat neuropsychiatricdisorders, including tardive dyskinesia and other movement disordersinduced by chronic exposure of patients to neuroleptic (antipsychotic)drugs. Tourette's syndrome, and mental disorders such as posttraumaticstress disorder (PTSD) and obsessive-compulsive disorder (OCD).

SUMMARY

A drug with extraordinary safety and a unique mode of CNS actionpotentially applicable to highly prevalent neurological and psychiatricdisorders would seem to be destined for great success. A new clinicalentity with such a story would undoubtedly generate significantscientific and commercial interest. Acamprosate, however, has not hadsuch success. The fact that it has been on the market and off-patent fora long time contributes to a lack of commercial interest. Morefundamentally, though, acamprosate's usefulness as a treatment for CNSdisorders is limited by the pharmacokinetic properties of the drug inits currently marketed formulation. That formulation, a 333 mgenteric-coated tablet (available under the trade name, Campral®) haspoor and variable bioavailability (11% on average) that is furtherreduced if the drug is taken with food, and it has poor gastrointestinal(GI) tolerability. If a patient takes the drug with food to mitigate GIside effects the consequence will be less absorption of the drug. Thelabeled dose of two tablets three times daily probably does not producetherapeutically adequate plasma levels of the drug in many patients,while taking six pills a day on a three-time-daily (TID) basis isalready a barrier to long-term treatment adherence, especially whenpatients are taking other drugs concurrently, and when the drug oftencauses gastrointestinal side effects.

Based upon the new innovation described herein, acamprosate has againbecome a clinically interesting drug—and perhaps a new option fortreating CNS disorders. As set forth below and without being limitedthereto, according to some embodiments acamprosate has been reformulatedso that: (1) One or two pills daily can be an effective dose; (2) It canbe taken with or without food with no adverse effect on bioavailabilityor efficacy; and/or (3) It infrequently has GI side effects, even whengiven at a significantly higher dosage per pill than thecurrently-marketed enteric-coated formulation.

The inventions herein show how acamprosate can be reformulated to attainone or more of these three properties. It might be thought that thiswould require increasing the bioavailability of the drug, and indeedsome unsuccessful past attempts to reformulate acamprosate attempted todo this. Some embodiments described herein relate to how the threecriteria for an improved formulation of acamprosate can be attained bytailoring the release kinetics of the formulation. By so doing GI sideeffects are mitigated, the food effect on pharmacokinetics (and not justbioavailability) is eliminated, and efficacy relative to the total dailymilligram dose is increased. The new formulations created in this wayare essentially new CNS drugs; the distinctive mechanism of action,remarkable safety, and potential for efficacy in a broad range of widelyprevalent CNS disorders make them a salient therapeutic advance.

In one aspect, the present application describes new formulations andmethods of using acamprosate that exhibit unpredictable and surprisingproperties. The new class of formulations addresses the drawbacks andlimitations of the currently marketed formulation, Campral®, therebyfacilitating the clinical use of acamprosate, alone or in combinationwith other drugs, for the treatment of neuropsychiatric disorders andother diseases and conditions. The new formulations can permit largerdosages of the drug in a single pill, better toleration with reducedand/or infrequent GI side effects, reduced or no food effect onbioavailability, similar bioavailability as Campral® taken without food,and significantly better bioavailability than Campral® is taken withfood—thus better bioavailability than Campral® on its usual TID basis inwhich at least one of the doses is taken with food or shortly aftereating.

Provided herein are sustained-release (SR) formulations of acamprosate.As used herein sustained-release formulations of acamprosate refer tothe sustained-release (SR) formulations described herein and exemplifiedin Examples 3 and 4. In some embodiments the new formulations can giveon average more than half of their 48-hour AUC in the first 12 hoursafter administration, while avoiding the high C_(max) that would beproduced by an immediate release (IR) preparation that give the same12-hour AUC. In some embodiments, the formulations provided herein alsohave the remarkable, unexpected, and therapeutically valuable propertyof fed-fasting equivalence, i.e., of having substantially the sameaverage AUC and C_(max) in the fed state and in the fasting state. Thisproperty allows patients to take the formulation without considerationof food intake, and in particular with meals—either always orsometimes—if doing so is better tolerated and/or if it is moreconvenient. This improves treatment adherence, and because it does sowith no negative impact on AUC or C_(max), it can improve theeffectiveness of the formulation as well as its efficacy.

The fed-fasting equivalence of formulations described herein wascompletely unpredictable and is remarkable. Given the known interferenceof food with the absorption of acamprosate, the site of sustainedrelease of acamprosate from the SR tablet in the fed state must favorthe extent and rate of acamprosate absorption to exactly the degree thatthe presence of food interferes with them. That these two factors shouldso exactly counterbalance each other was an unforeseen and wonderfuldiscovery.

The formulations according to some embodiments retain their integrityfor several hours in solution, releasing acamprosate by diffusion at arate proportional to the square root of time. In some embodiments,without being limited thereto, the desirable release kinetics andfed-fasting equivalence of those kinetics, can result from suchdiffusion characteristics.

In some embodiments the new formulations or compositions include a highmolecular weight polymer of acrylic acid, which also can be referred toas polyacrylic acid (“PAA”). Such polymers include a class of compoundscalled “carbomers,” which include polymers with varying degrees ofcrosslinking, for example, with allyl ethers of polyalcohols. Examplesof commercially available carbomers include those referred to asCarbopol® polymers (available from The Lubrizol Corporation, USA).Several examples of Carbopol® compounds that can be included with thenew formulations are those available under the brand names Carbopol®971P (carboxypolymethylene; carbomer homopolymer type A—lightlycross-linked with allyl ethers of pentaerythritol) and Carbopol® 974P(carboxypolymethylene; carbomer homopolymer type B—highly cross-linkedwith allyl ethers of pentaerythritol). The formulations further caninclude variable amounts of other pharmacologically suitableingredients. In these compositions the weight of acamprosate may greatlyexceed the total weight of the excipients, permitting the formulation oftablets small enough to easily swallow that contain significantly moreacamprosate than any marketed formulation. (The largest dose ofacamprosate calcium marketed in the US is 333 mg; a 500 mg pill is soldin other countries. By contrast, one example the formulations providedherein may contain 800 mg of acamprosate calcium in one tablet. Theidentification of a carbomer as a principal excipient, for someembodiments, to produce these kinetics was an unpredictable andsurprising discovery. There are numerous choices for excipients forsustained release preparations and no a priori certainty that aparticular one used at a particular ratio of API to excipient, withparticular additional ingredients, will produce a specific desired invivo pharmacokinetic profile, let alone result in fed-fastingequivalence of both C_(max) and AUC when the API as an (immediaterelease) solution as well as the marketed product show a large foodeffect on drug absorption.

In some embodiments the compositions can include medications, such asneuroleptic (antipsychotic) and/or antidepressant drugs, combined withthe improved acamprosate formulations. Also disclosed are methods ofusing the improved formulations or compositions in treating diseases anddisorders, including movement disorders and other neuropsychiatricdisorders. Some embodiments relate to improved compositions and methodsof using the same where the compositions can be administered in either afed or fasted state.

In one aspect, provided is a composition comprising less than or equalto about 1500 mg of a pharmaceutically acceptable salt of acamprosateand a carbomer polymer.

In some embodiments, the composition comprises less than about 1000 mgof the pharmaceutically acceptable salt of acamprosate. In someembodiments, the composition comprises about 800 mg of thepharmaceutically acceptable salt of acamprosate. In some embodiments,the composition comprises about 400 mg of the pharmaceuticallyacceptable salt of acamprosate. In some embodiments, the compositioncomprises about 1000 to 1500 mg of the pharmaceutically acceptable saltof acamprosate.

In some embodiments, the pharmaceutically acceptable salt of acamprosateis about 20% to about 90% of the total weight of the composition.

In some embodiments, the pharmaceutically acceptable salt of acamprosateis acamprosate calcium.

In some embodiments, the carbomer polymer is present at from about 1% toabout 25% of the total weight of the composition. In some embodiments,the composition comprises about 10 mg to about 200 mg of the carbomerpolymer. In some embodiments, the composition comprises the carbomerpolymer is a cross-linked polyacrylic acid. In some embodiments, thecarbomer polymer is Carbopol 971P. In some embodiments, the carbomerpolymer is Carbopol 974P.

In some embodiments, the composition further comprises a firstgeneration antipsychotic, a second generation antipsychotic, a selectiveserotonin reuptake inhibitor or a serotonin norepinephrine reuptakeinhibitor. In some embodiments, the composition further comprises asecond medication selected from the group consisting of thioridazine,chlorpromazine. thiothixene, trifluoperazine, fluphenazine, haloperidol,perphenazine, loxapine, molindone, metoclopramide, aripiprazole,asenapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone, ziprasidone, citalopram, desvenlafaxine,duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,paroxetine, sertraline, venlafaxine, or a combination thereof.

In another aspect, provided is a pharmaceutical composition comprisingabout 20% to about 90% by weight of pharmaceutically acceptable salt ofacamprosate and an amount of a carbomer polymer sufficient to provideabout 30% or more of the 48-hour AUC by 8 hours after administration.

In another aspect, provided is a unit dose of a pharmaceuticalcomposition comprising up to about 1500 mg of acamprosate calcium oranother pharmaceutically acceptable salt of acamprosate and an effectiveamount of a carbomer polymer, wherein the plasma exposure following asingle dose of acamprosate is at least 100 ng mL for 8 hours and is atleast 250 ng/mL for 6 hours in a subject to whom the composition hasbeen administered.

In some embodiments, the unit dose composition comprises less than about1000 mg of the pharmaceutically acceptable salt of acamprosate. In someembodiments, the unit dose composition comprises about 800 mg of thepharmaceutically acceptable salt of acamprosate. In some embodiments,the unit dose composition comprises about 400 mg of the pharmaceuticallyacceptable salt of acamprosate. In some embodiments, the unit dosecomposition comprises about 1000 to 1500 mg of the pharmaceuticallyacceptable salt of acamprosate.

In some embodiments, the pharmaceutically acceptable salt of acamprosateis acamprosate calcium.

In some embodiments, the unit dose composition has been administered inthe fasted state. In some embodiments, the unit dose composition hasbeen administered in the fed state.

In another aspect, provided is a method of treating a disease, disorder,symptom, or syndrome in a patient in need of such treatment comprisingadministering to said patient the composition or unit dose compositiondescribed above.

In another aspect, provided is a method of treating a neuropsychiatricdisorder in a patient, comprising administering to a patient acomposition or unit dose composition described above.

In some embodiments, administration to the patient in a fed state and ina fasted state produces substantially bioequivalent acamprosate plasmaC_(max) values. In some embodiments, administration to the patient in afed state and in a fasted state produces bioequivalent acamprosateplasma T_(max) values. In some embodiments, administration to thepatient in a fed state and in a fasted state produces bioequivalentacamprosate plasma AUC values.

In still another aspect, provided is a method of maintaining an in vivosteady-state acamprosate plasma concentration at or above a minimumlevel needed for therapeutic efficacy for a neuropsychiatric or othermedical condition in a patient in need thereof, wherein the plasmaconcentration in steady state is above the minimum level at least 4-10hours out of a 24 hour period, the method comprising administering tothe patient a dosage of a pharmaceutically acceptable salt ofacamprosate comprising up to about 1500 mg of acamprosate, and whereinthe pharmaceutically acceptable salt of acamprosate is formulated in apolymer matrix that releases acamprosate by diffusion, and the dosage isadministered either once daily or twice daily, either with or withoutfood.

In some embodiments, the dosage comprises less than about 1000 mg of thepharmaceutically acceptable salt of acamprosate. In some embodiments,the dosage comprises about 400 mg of the pharmaceutically acceptablesalt of acamprosate. In some embodiments, the dosage comprises about 800mg of the pharmaceutically acceptable salt of acamprosate. In someembodiments, the dosage comprises about 1000 to 1500 mg of thepharmaceutically acceptable salt of acamprosate.

In some embodiments, the pharmaceutically acceptable salt of acamprosateis formulated in a polymer matrix that releases, by diffusion in vitro,approximately 50% of the acamprosate within 2 hours and releases atleast 80% of the acamprosate within 4 hours.

In some embodiments, the steady-state in vivo acamprosate plasmaconcentration is maintained at or above a threshold for therapeuticefficacy for at least 4-10 hours out of a 24 hour period, wherein thetherapeutic threshold is about 100 ng/mL to about 500 ng/mL.

In some embodiments, the steady-state in vivo acamprosate plasmaconcentration is maintained at or above a threshold for therapeuticefficacy for at least six hours out of a 24 hour period, wherein thetherapeutic threshold is about 200 ng/mL. In some embodiments, thesteady-state in vivo acamprosate plasma concentration is maintained ator above a threshold for therapeutic efficacy for at least six hours outof a 24 hour period, wherein the therapeutic threshold is about 300ng/mL. In some embodiments, the in vivo acamprosate plasma level is ator above the therapeutic level for at least 8 hours.

In some embodiments, the pharmaceutically acceptable salt of acamprosateis acamprosate calcium.

In still another aspect, provided is composition comprising apharmaceutically acceptable salt of acamprosate and a first generationantipsychotic or a second generation antipsychotic agent.

In some embodiments subject matter described in PCT/US2012/067507, filedDec. 2, 2012 is specifically excluded, including one or more of thespecific formulations described or claimed therein.

The foregoing is a summary and thus contains, by necessity,simplifications, generalization, and omissions of detail; consequently,those skilled in the art will appreciate that the summary isillustrative only and is not intended to be in any way limiting. Otheraspects, features, and advantages of the devices and/or processes and/orother subject matter described herein will become apparent in theteachings set forth herein. The summary is provided to introduce aselection of concepts in a simplified form that are further describedbelow in the Detailed Description. This summary is not intended toidentify key features or essential features of the claimed subjectmatter, nor is it intended to be used as an aid in determining the scopeof the claimed subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

Features, aspects, and advantages of the present invention will becomeapparent from the following description, and the accompanying exemplaryembodiments shown in the drawings, which are briefly described below

FIGS. 1-4 shows the release profile of tablets of Example 4 in acetatesolution (pH 4.5) or 1M HCl (pH 1.0).

FIG. 5 shows the plasma concentrations of Campral® and 800 mg sustainedrelease formulation and 400 mg sustained release formulation of Example3 when administered in the fed state (30 minutes after a high-fat meal).

FIG. 6 shows the arithmetic mean acamprosate plasma concentration-timeprofiles following administration of oral doses of 800 mg sustainedrelease tablet to humans under fed and fasting conditions—linear scale.

FIG. 7 shows the arithmetic mean acamprosate plasma concentration-timeprofiles following administration of oral doses of 800 mg sustainedrelease tablets and Campral® 666 mg tablets under fastingconditions—linear scale.

FIGS. 8 and 9 show gamma scintigraphy images of a tablet describedherein in the GI tract of a subject who was administered the tablet infasted and fed state.

FIG. 10 shows that the diffusion kinetics of tablets of Example 3 indifferent form are similar.

DETAILED DESCRIPTION

Acamprosate (bis acetyl-homotaurine; [3-(acetylamino)-1-propanesulfonicacid]; N-acetyl homotaurine) has effects on both glutamate-mediated andGABA-mediated neurotransmission. Acamprosate is a compound with highsolubility and low permeability—Class III under the BiopharmaceuticalsClassification System (BCS). The bioavailability of BCS Class IIIcompounds tends to be low because the absorption of such compoundsoccurs either via diffusion—which is slow and inefficient because of thelow permeability—or via specialized transporters in the membranes ofintestinal mucosal cells—which may not exist, may poorly bind thecompound, or may be easily saturated, implying zero-order kinetics. Itis approved in several countries for the treatment ofalcoholism—specifically, the inhibition of craving for alcohol inalcohol-dependent patients who are currently abstinent. Acamprosate haslimited effectiveness for treating alcoholism. Some controlled studieshave failed to show efficacy, and adoption of the drug in practice hasnot been widespread.

Acamprosate is commonly used in the form of its calcium salt. Otherpharmaceutically acceptable salt of acamprosate can also be used. Suchsalts include acamprosate salts of inorganic bases, for example,alkaline metals such as sodium or potassium; salts of other alkalineearth metals such as magnesium; salts of organic bases, for example,trimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine. It should be understood that in themethods, uses and compositions described herein, that acamprosatecalcium can be substituted for, by, or included with any other salt oranalog, for example, one or more of sodium N-acetylhomotaurine,magnesium N-acetylhomotaurine, lithium N-acetylhomotaurine, or any otherforms of N-acetylhomotaurine, at the same milligram dose and/or freeacid equivalent dose. Unless otherwise stated, acamprosate refers toacamprosate calcium. However, this disclosure is not limited toacamprosate calcium and other pharmaceutically acceptable salts ofacamprosate, such as those described above, can be used to substituteacamprosate calcium.

As noted above, the acamprosate calcium enteric-coated dosage formcurrently marketed in the United States is sold under the trade nameCampral® and by various other trade names (e.g., Aotal™, Regtect™) inother countries. Each Campral® tablet contains 333 mg acamprosatecalcium, which is equivalent to 300 mg acamprosate. These tablets areformulated as enteric coated tablets, with the labeled dose being 2tablets, 3 times daily. It is noted on the label that taking Campral®with food impairs its bioavailability although the label does notrequire that the drug be taken without food.

As previously noted, embodiments herein generally relate to improvedformulations of acamprosate, as well as to methods of using the same.Some embodiments relate to the unexpected and surprising discovery ofnew classes of formulations that provide various unexpected advantages,as discussed more fully herein. In some aspects the improvedformulations and methods can permit the use of acamprosate to treatvarious disorders while permitting one more of the following (withoutbeing limited thereto): (1) the use of the compositions in either a fedor a fasted state with equal therapeutic efficacy, which is a newdiscovery; (2) the use of lower total daily dosages, feweradministrations per day and/or fewer pills per administration, which canlead to greater compliance and greater efficacy; (3) less frequentand/or less severe gastrointestinal side effects; and (4) the use ofacamprosate (or another pharmacologically-acceptable salt ofN-acetylhotnotaurine) in combination formulation with anothermedication, which was not feasible or practicable prior to the instantcompositions and methods. The compositions and methods arc described inadditional detail herein.

Definitions

The term “subject” or “patient” as used herein, refers to any animalsuch as a human.

The term “treating,” “treat,” “treatment” or the like, refers to any orall of an alleviation or elimination of one or more symptoms associatedwith a disease, disorder, or condition, halt or slowing of furtherprogression or worsening of the disease, disorder, or condition,including its symptoms, or prevention or prophylaxis of the disease,disorder, or condition, such as reducing the risk of or delaying theoccurrence of the disease, disorder, or condition in a subjectdetermined to be predisposed to the disease, disorder, or condition butnot yet diagnosed as having the disease, disorder, or condition. Forexample, within the context of tardive dyskinesia (TD), treatment mayinclude an alleviation of symptoms of TD, such as involuntary,irregularly rhythmic movements, or halting or slowing the progression ofthe disease, as measured by a reduction or cessation of the involuntary,irregularly rhythmic movements or preventing the worsening of symptomsrelating to the aging of the patient or the discontinuation ofantipsychotic medication, or prevention or prophylaxis of TD, such asreducing the risk of occurrence or worsening of TD in a subject who ison an antipsychotic drug or other dopamine receptor blocking drug for aperiod of time.

As used in the specification and claims, the singular form “a,” “an” and“the” include plural references unless the context clearly dictatesotherwise.

As used herein, the term “comprising” is intended to mean that thecompositions and methods include the recited elements, but do notexclude others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination when used for the intendedpurpose. Thus, a composition consisting essentially of the elements asdefined herein would not exclude trace contaminants or inert carriers.“Consisting of” shall mean excluding more than trace elements of otheringredients and substantial method steps. Embodiments defined by each ofthese transition terms are within the scope of this invention.

The term “about” as used herein in conjunction with a stated numericalvalue, refers to a value within ±10%, ±5% or ±1% of the stated numericalvalue.

The term “substantially” means within 80% to 120%, or 90% to 110%, or95% to 105% range of a reference value or any sub value or sub rangethere between.

The term “substantially equivalent” or “substantially the same” or thelike when describing a value, such as release rate, means that at thesame relative time point the value does not differ by more than 1% to20% or any sub value or sub range there between (e.g., 5%, 10%, 20%,etc.). For example, when the release rate of a composition in a pH 1.0solution is from about 80% to 120% of the release rate of thecomposition in a pH 4.5 solution when measured at the same time pointcalculated from the time when the composition is added to the solutions,then the composition has a substantially equivalent release rate at pH1.0 and pH 4.5 at that particular time point. If the composition had anequivalent release rate at pH 1.0 and pH 4.5 at no less than 90% of thetotal time points within the range of determination, then thecomposition would be said to have an equivalent release profile at pH1.0 and pH 4.5. In some embodiments when describing a PK profile, suchas T_(max), C_(max), or AUC, two values are considered to besubstantially the same if they meet the bioequivalence definition as setforth by a regulatory agency, such as the U.S. Food and DrugAdministration (FDA), the European Medicines Agency (EMA), and theAustralian Therapeutics Goods Administration (TGA).

The term “substantially intact” means that the shape and size of thecomposition (such as a pill or tablet) remain substantially the same asthe original shape and size of the composition in that each dimension iswithin 80% to 120%, or 90% to 110%, or 95% to 105% range ofcorresponding original dimension, or any sub value or sub range therebetween.

The term “AUC” is an abbreviation for “area under the curve” in a graphof the acamprosate concentration over time in a certain part or tissue,such as blood or plasma or, if applicable, in another body fluid such ascerebrospinal fluid, of a subject to whom acamprosate has beenadministered.

The term “C_(max)” is an abbreviation that refers to the maximumobserved concentration of acamprosate in a certain part or tissue, suchas blood or plasma (or, if applicable, in another body fluid), of asubject to whom acamprosate has been administered.

The term “T_(max)” is an abbreviation that refers to the time point whenthe time the maximum observed concentration of acamprosate is reached ina certain part or tissue, such as blood or plasma or, if applicable, inanother body fluid, of a subject to whom acamprosate has beenadministered.

The term “T_(1/2)” is an abbreviation that refers to the time periodrequired for the concentration of acamprosate in blood or plasma (or, ifapplicable, in another body fluid), to fall to one-half of its initialvalue, in the absence of administration of any additional drug.

Unless otherwise specified, the various in vitro dissolution values, andpharmacokinetic values, such as AUC, C_(max), T_(max), T_(1/2), releaserate, etc., used herein are average values of a typical population ofsubjects and the values of a particular individual subject may vary ascan be appreciated by a person skilled in the art.

The term “other medication” refers to any compound or composition thatis approved or will be approved for administration to a human in anymanner by any regulatory agency, such as the FDA, EMA and TGA. In someembodiments, the other medication is not contraindicated foracamprosate. In some embodiments, the other medication is a medicationfor the treatment of a disease which acamprosate is intended to treat.

The term “confidence interval” or “CI” as used herein has its ordinarymeaning, such as used in defining bioequivalence by a regulatory agency,such as the FDA, EMA and TGA. A confidence interval is specified by thepercentage of cases that lie within the interval.

The term “fed state” refers to a state of a subject wherein there isfood in the stomach of the subject such that the release and/orabsorption of acamprosate from the a formulation can be affected ascompared with when there is no food in the stomach. In some embodiments,a fed state is the state of the subject during the time from the startof food consumption to about 2 hours after food consumption, such asduring food consumption, immediately after food consumption, about 30minutes after food consumption, about 1 hour after food consumption,about 1.5 hours after food consumption, or about 2 hours after foodconsumption, or any time between any of the two numbers, end pointsinclusive. As used herein, food consumption refers to consuming asubstantial amount of food, such as at least one third of a normal mealof a subject, either by volume or by total number of calories consumed.

The term “fasted state” refers to a state of a subject wherein there issubstantially no residual food in the stomach of the subject. In someembodiments, a fasted state is the state of the subject during the timefrom about 2-3 hours after food consumption to about 30 minutes beforethe next food consumption, such as 3 hours after food consumption, 3.5hours after food consumption, 4 hours after food consumption, or 30minutes before the next food consumption, or any time between any of thetwo numbers, end points inclusive.

Formulations

As already noted above, various embodiments relate to formulationscomprising acamprosate. For example, some embodiments relate to unitdosage forms and pharmaceutical compositions comprising acamprosatecalcium or another pharmaceutically acceptable salt thereof, and methodsof treatment using the same.

A sufficient brain level of acamprosate is needed for treating certaindisorders such as craving in abstinent alcoholics or neuropsychiatricdisorders such as tardive dyskinesia and other movement disorders.However, the brain levels needed for therapeutic effect in theseconditions are in many subjects difficult to attain using existingformulations, such as the marketed formulation (Campral®) without givingtotal daily dosages of 2-4 grams or more. If administered three timesper day (TID), this daily dosage of Campral® would require two to four333 mg pills per administration. Such doses are burdensome and createtreatment adherence issues. Further, the existing dosage forms have poorgastrointestinal (GD tolerability with patients complaining of nausea,vomiting, and diarrhea, and many discontinuing the medication or takingit irregularly because of the side effects. For example, the c packageinsert reports that 10% of patients taking 1332 mg per day of Campral®had diarrhea and 17% of patients taking 1998 mg a day (two 333 mgtablets TID) had diarrhea; overall, 28% of patients taking Campral® hada GI side effect of some kind.

Poor tolerability of taking Campral® that causes GI irritation may beimproved by taking the medication with meals. However, in the case ofthe Campral® formulation, taking the medication with food reduces itsbioavailability by approximately 23% and its C_(max) by approximately42%, implying a substantial effect on the residence time of the drug ata potentially therapeutic blood level. In another study, it was foundthat both bioavailability and C_(max) in the first 48 hours reduced byabout 41% on average when the Campral® formulation was taken in a fedstate than in a fasted state. In particular, the significantly reducedC_(max) may result in that the plasma concentrations of acamprosate willnot be within a therapeutically effective range when a normal dosage ofthe Campral® formulation is administered in a fed state. All of thesefactors lead to Campral® being a less than ideal formulation ofacamprosate for the treatment of neuropsychiatric conditions.

Some embodiments herein relate to formulations of acamprosate that canattain adequate central nervous system (CNS) levels of the drug, arewell tolerated, and can be administered once or twice a day. In someaspects, the formulations permit the administration of a single pill ortablet once or twice a day. In some aspects the formulations can includemore than 333 mg or more than 500 mg of acamprosate calcium in a singlepill. Such formulations can contain a large amount of acamprosate, yetcan be swallowed easily, and/or can have good GI tolerability.

Accordingly, some embodiments described herein relate to the surprisingand unexpectedly effective discovery of formulations suitable, forexample, as pills or tablets that have more than 333 mg or more than 500mg of acamprosate calcium and have a reasonable size that can beswallowed. Such embodiments include a combination of excipients thatprovide the pill or tablet with physical integrity and desired releasekinetics with the least mass and volume. Surprisingly, such compositionscomprising up to 800 mg or more (such as 1.5 g) of acamprosate calciumin a tablet that is small enough to swallow can be obtained usingformulations that maintain their integrity for a sufficient period oftime and release the active ingredient at rate substantially equal tothe square root of time.

In some embodiments, the formulations include a polymer such as apolyacrylic acid polymer, preferably carbomers. As noted above,carbomers include acrylic acid polymers with varying degrees ofcrosslinking, for example, with allyl ethers of polyalcohols.

In some embodiments, carbomers can be depicted as

is cross linking group, such as alkylene, allylsucrose or allylpentaerythritol, each R^(I) is independently hydrogen or CH₃, each R² isindependently hydrogen or C₁-C₃₀alkyl, and x, y and n are independentlyan integer which can be as much as to produce a polymer having amolecular weight of up to 4.5 billion. Formulas 11 and 111 can becross-linked with a cross linking group such as alkylene, allylsucroseor allyl pentaerythritol.

In some embodiments, the average molecular weight of carbomer is about10,000 to 1,000,000, such as about 10,000, 50,000, 100,000, 200,000,500,000, 700,000, 1,000,000, or any ranges between two of the values,end point inclusive. In some embodiments, n is a integer of 500 to 5000,1000-2000, 2000-3000, 3000-4000, or 4000-5000, or any value or subrangetherebetween.

Examples of commercially available carbomers include those referred toas Carbopol® polymers(available from The Lubrizol Corporation, USA).Several non-limiting examples of Carbopol® compounds that can beincluded with the new formulations are those available under the brandnames Carbopol® 971P (carboxypolymethylene; carbomer homopolymer typeA—lightly cross-linked with allyl ethers of pentaerythritol) andCarbopol® 974P (carboxypolymethylene; carbomer homopolymer type B—highlycross-linked with allyl ethers of pentaerythritol). The formulationsfurther can include additional excipients and ingredients. Additionalpolymers optionally can be included such as carboxymethylcellulose(CMC).

Without being limited thereto, it is worth noting that such formulationssurprisingly and unexpectedly can provide a number of advantages. Forexample, in some non-limiting aspects, the formulations can permit theadministration of acamprosate with or without food, or in a fed or afasted state, with an equal expectation of therapeutic efficacy In somenon-limiting aspects the formulations can provide substantiallyequivalent pharmacokinetics, and substantial equivalence in therapeuticefficacy. Such a discovery is quite unexpected in view of the fact thatexisting formulations have been reported to have significant (e.g., 23%or more) decrease in bioavailability in the presence of food, which canlead to poorer therapeutic efficacy, and data from a pharmacokineticstudy of Campral® in healthy male volunteers reported herein suggeststhat the 23% reported decrease in bioavailability in the fed state maybe an underestimate in populations of clinical interest.

Accordingly, in one aspect, the technology described herein provides aunit dose of a pharmaceutical composition comprising up to 1.5 grams ofa pharmaceutically acceptable salt of acamprosate and a carbomerpolymer. In some embodiments, the pharmaceutically acceptable salt ofacamprosate is acamprosate calcium. The dosage form can be in an oralform, such as a pill or tablet or any other embodiment that can beswallowed by the patient.

In some embodiments, the composition may include, for example, about 400mg to 1500 mg or about 600 mg to 1500 mg of acamprosate orpharmaceutically acceptable salt thereof (or any value or ranges betweenany two numbers, end points inclusive). For example, the amount ofacamprosate (or a pharmaceutically acceptable salt thereof) can be about400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg,about 1400 mg, about 1500 mg. In some embodiments, the unit dose of apharmaceutical composition can include less than about 1000 mg ofacamprosate or a pharmaceutically acceptable salt thereof.

In some embodiments, the acamprosate calcium or another pharmaceuticallyacceptable salt thereof is about 20% to about 95% of the total weight ofthe composition (or any value or range between those numbers, end pointsinclusive). In some embodiments, the acamprosate calcium or anotherpharmaceutically acceptable salt thereof is about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 72%, about 75%, about 80%,or about 90% of the total weight of the composition, or any value orranges between any two of e numbers (end points inclusive).

As noted above, in some embodiments, the carbomer polymer is across-linked polyacrylic acid. In some embodiments, the carbomer polymeris carbomer homopolymer Type A. In some embodiments, the carbomerpolymer is carbomer homopolymer Type B. In some embodiments, thecarbomer is a carbomer having viscosity of from about 4,000 to about39,400, or from about 4,000 to about 11,000, or from about 29,400 toabout 39,400 cP as a 0.5 wt % aqueous solution at pH 7.3-7.8. In someembodiments, the carbomer polymer is Carbopol® 971P, available from TheLubrizol Corporation, USA. In some embodiments, the carbomer polymer isCarbopol® 974P, available from The Lubrizol Corporation, USA.

In some embodiments, the unit dose of a pharmaceutical compositioncomprises the carbomer in an amount that provides a T_(max) of 1-4 hoursin the fasting state, and 2-5 hours in the fed state, a human to whomthe composition has been administered.

In some embodiments, the carbomer polymer is present at from about 1% toabout 30% of the total weight of the composition (or any value or rangethere between, end points inclusive). In some embodiments, thepolyacrylic acid polymer or the carbomer polymer is present at about 1%,about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%,about 22%, about 23%, about 24%, or about 25% of the total weight of thecomposition, or any value or ranges between any two of the numbers (endpoints inclusive).

In some embodiments, the unit dose of the pharmaceutical compositioncomprises about 10 mg to about 300 mg of the carbomer polymer (or anyvalue or range there between, end points inclusive). In someembodiments, unit dose comprises about 10 mg, about 20 mg, about 30 mg,about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, or about 200mg of the carbomer polymer, or any ranges between any two of the numbers(end points inclusive).

In some embodiments, provided is a unit dose of a pharmaceuticalcomposition comprising up to about 1500 mg of acamprosate calcium, oranother pharmaceutically acceptable salt thereof, and an effectiveamount of a carbomer polymer, wherein the plasma exposure in a humanfollowi g administration of the unit dose to the human is at least 100ng/mL for 8 hours and is at least 250 ng/mL for 6 hours. In someembodiments, the plasma exposure is at least 150 ng/mL for 8 hours, atleast 200 ng/mL for 8 hours, at least 250 ng/mL for 8 hours, or at least300 ng/mL for 6 hours, or a range between any two of the plasma exposurevalues, end points inclusive.

In some embodiments, the unit dose of the composition can beadministered in the fasted state. In some embodiments, the unit dose ofthe composition can be administered in the fed state. In someembodiments administration in one of the fed or fasted states canspecifically be excluded. In some embodiments the unit dose can beadministered for therapeutic purposes in either the fed or the fastedstate, with the subject having the option for each individual dose as towhether to take it with or without food. In some embodiments the unitdose of the composition can be administered immediately prior to foodintake (e.g., within 30 or within 60 minutes before), with food, rightafter food intake (e.g., within 30, 60 or 120 minutes after foodintake). In some embodiments, it can be administered, for example, atleast 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours, or more after food intake, or anytime there between. In some embodiments, the unit dose of thecomposition is administered after overnight fasting. In some embodimentsthe unit dose of the composition can be administered 30 minutes beforefood intake, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or more beforefood intake, or any time there between.

In some embodiments, the formulation provide substantially the same(bioequivalent) release profile of acamprosate whether administered in afed or fasted state, with or without food, or at any time describedabove.

In some embodiments, provided is a composition comprising about 20% toabout 90% by weight of acamprosate or another pharmaceuticallyacceptable salt of N-acetylhomotaurine and an amount of a carbomerpolymer sufficient to provide a T_(max) of acamprosate in plasma fromabout 1 hours to about 6 hours. In some embodiments, provided is acomposition comprising up to about 800 mg of a pharmaceuticallyacceptable salt of acamprosate, which is about 20% to about 90% byweight of the total weight of the composition, and an amount of acarbomer polymer sufficient to provide a plasma C_(max) of acamprosatefrom about 200 ng/mL to about 500 ng/mL. In some embodiments, providedis a composition comprising up to about 1200 mg of a pharmaceuticallyacceptable salt of acamprosate, which is about 20% to about 90% byweight of the total weight of the composition, and an amount of acarbomer polymer sufficient to provide a plasma C_(max) of acamprosatefrom about 200 ng/mL to about 750 ng/mL.

In some embodiments, the unit dose or the pharmaceutical composition mayfurther include a swellable hydrophilic polymer. Such polymers swellrather than dissolve when in contact with water. Examples of swellablehydrophilic polymers include cellulosic hydrocolloids such asmethylcellulose (MC), hydroxypropylcellulose (HPC),hydroxymethylcellulose (HPMC), hydroxy-ethylcellulose (HEC),carboxymethylcellulose (CMC), carboxymethylcellulose sodium (NaCMC) andcarboxyethylcellulose (CEC), or mixtures thereof. In one embodiment, theswellable hydrophilic polymer is carboxymethylcellulose.

In some embodiment, the unit dose or pharmaceutical composition furthercomprises a suspension agent, such as crosscarmellose.

In some embodiments, the formulations does not include one or moreabsorption-promoting agents. In some embodiments, theabsorption-promoting agent can be one or more lipid substances selectedfrom polysorbates, ethers of polyoxyethylene and alkyl, esters ofpolyoxythylene and fatty acids, fatty alcohols, bile acids and theirsalts with pharmaceutically acceptable cations, esters of C₁-C₆ alkanolswith fatty acids, esters of a polyol with fatty acids wherein saidpolyol comprises 2 to 6 hydroxyl groups, and polyglycolysed glycerides.In some embodiments, the absorption-promoting agent has ahydrophilic-lipophilic balance (HLB) value of greater than 8. It shouldbe understood that in some embodiments the formulations can specificallyexclude an absorption promoting agent, including one or moreabsorption-promoting agents described herein.

The unit dose or the pharmaceutical composition may further include anelastomer. Suitable elastomers are known in the art and include,thermoplastic polyurethane elastomers or thermoplasticpolycarbonate-urethanes, e.g., Carbosil® (thermoplastic siliconepolycarbonate polyurethane available in several versions from DSMBiomedical, USA).

The unit dose or the pharmaceutical composition may further include aglidant. Suitable glidants are known in the art and include silicondioxide, colloidal silicon dioxide, fumed silicon dioxide, calciumsilicate, corn starch, magnesium carbonate, asbestos free talc, metallicstearates, calcium stearate, magnesium stearate (MGST), zinc stearate,stcarowct C™, starch, starch 1500, magnesium lauryl sulfate, andmagnesium oxide, or mixtures thereof. In one embodiment, the glidant iscolloidal silicon dioxide. In some embodiments, the colloidal silicondioxide is present in the composition in an amount of 0.01 to about10.0% w/w, about 0.05 to about 5.0% w/w, about 0.02 to about 3.0% w/w,or about 0.1 to about 1.5% w/w.

The unit dose or the pharmaceutical composition may further include alubricant. Suitable lubricants are known in the art and includemagnesium stearate, calcium stearate, sodium stearyl fumarate, stearicacid, hydrogenated vegetable oil, glyceryl behenate, and polyethyleneglycol, or mixtures thereof. Tn one embodiment, the lubricant ismagnesium stearate. In some embodiments, the magnesium stearate ispresent in the composition in an amount of about 0.01 to about 10.0%w/w, about 0.1 to about 5.0% w/w, about 0.2 to about 3.0% w/w, or about0.25 to about 1.5% w/w.

The unit dose or the pharmaceutical composition may further include adisintegrant or a supplemental binder. Suitable disintegrants are knownin the art and include crosscarmellose sodium, sodium starch glycolate,crospovidone, microcrystalline cellulose, pregelatinized starch,cornstarch, alginic acid, and ion exchange resin. In one embodiment, thedisintegrant is Starcap® 1500 (co-processed mixture of globally acceptedexcipients, corn starch and pregelatinized starch; available fromColorcon, USA).

In some embodiments, the unit dose or the pharmaceutical compositioncomprises, consists essentially of, or consists of a high molecularweight swellable polymer, such as carbomer (e.g., Carbopol 974P® orCarbopol 971P®), and one or more excipients selected frommicrocrystalline cellulose (e.g., Avicel PH102 or Avicel PH10),carboxymethylcellulose (e.g., CMC 7HF), vinyl pyrrolidone, PovidoneK-90, silicon dioxide (e.g. Cabosil), colloidal silicon dioxide, fumedsilicon dioxide, calcium silicate, magnesium carbonate, asbestos freetalc, talc, metallic stearates, citric acid, calcium stearate, magnesiumstearate, zinc stearate, starch (e.g., StarCap 1500), starch 1500,magnesium lauryl sulfate, magnesium oxide, and water. In one embodimentmicrocrystalline cellulose is present in an amount of about 5 to about40% weight/weight (w/w), such as about 5, about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40% or any ranges betweenany two of the values, end points inclusive. In some embodiments, eachof colloidal silicon dioxide, citric acid, carboxymethylcellulose,starch, talc, magnesium stearate, vinyl pyrrolidone, and silicondioxide, if present, is present in the composition in an amount of 0.01to about 10.0% w/w, about 0.05 to about 5.0% w/w, about 0.02 to about3.0% or about 0.1 to about 1.5% w/w.

The unit dose or the pharmaceutical composition may be provided in theform of a tablet, a film coated tablet, a pill, a gel cap, a caplet, ora bead. In one embodiment, the composition is in the form of a sphericaldisc shaped tablet. In one embodiment, the composition is in the form ofan oval shaped tablet. In one embodiment, the composition is in the formof an oblong shaped tablet.

In some embodiments, the pharmaceutical composition described hereinfurther comprises one or more other medications, such as a firstgeneration antipsychotic, a second generation antipsychotic, a selectiveserotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrinereuptake inhibitor (SNRI). In some embodiments, the pharmaceuticalcomposition described herein can be administered with one or more othermedications, such as a first generation antipsychotic, a secondgeneration antipsychotic, a selective serotonin reuptake inhibitor or aserotonin norepinephrine reuptake inhibitor.

For example, a composition as described herein can further comprise orbe administered with at least a second medication that includes one ormore of an antipsychotic (neuroleptic) medication, a selective serotoninreuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor(SNRI), an antidepressant other than an SSRI or SNRI, an anti-anxietymedication other than an SSRI or SNRI or the like; or the anti-nauseadrug metoclopramide The antipsychotic medication can be, for example, afirst or a second generation antipsychotic. The first or a secondgeneration antipsychotic can be for example, one or more ofthioridazine, chlorpromazine, thiothixene, trifluoperazine,fluphenazine, haloperidol, perphenazine, loxapine, molindone,aripiprazole, asenapine, iloperidone, lurasidone, olanzapine,paliperidone, quetiapine, risperidone, ziprasidone, and the like. TheSSRI or SNRI can be, for example, one or more of citalopram,desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine,milnacipran, paroxetine, sertraline, venlafaxine, and the like. Theproduct may include, for example, a single dosage form unit thatincludes, consists or consists essentially of both acamprosate and atleast one second medication.

In some embodiments, the pharmaceutical composition described hereinfurther comprises one or more other medications are selected from thegroup consisting of thioridazine, chlorpromazine, thiothixene,trifluoperazine, fluphenazine, haloperidol, perphenazine, loxapine,molindone, aripiprazole, asenapine, iloperidone, lurasidone, olanzapine,paliperidone, quetiapine, risperidone, ziprasidone, citalopram,desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine,milnacipran, paroxetine, sertraline, venlafaxine or metoclopramideor acombination thereof. In some embodiments, the pharmaceutical compositiondescribed herein can be administered with one or more other medicationsselected from the group consisting of thioridazine, chlorpromazine,thiothixene, trifluoperazine, fluphenazine, haloperidol, perphenazine,loxapine, molindone, aripiprazole, asenapine, iloperidone, lurasidone,olanzapine, paliperidone, quetiapine, risperidone, ziprasidone,citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine,fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, ormetoclopramide, or other medications described herein, or a combinationthereof.

In some embodiments, the composition of acamprosate described hereinfurther comprises prazosin. In some embodiments, prazosin is in theamount of from about 1 mg to 15 mg, such as about 1 mg, 5 mg. 10 mg, or15 mg, or any ranges between any two values. In some embodiments,acamprosate is in the amount of deom about 400 mg to 1500 mg, such asabout 400 mg, 500 mg, 800 mg, 1000 mg, 1300 mg, or 1500 mg, or anyranges between any two values. Prazosin (trade names Minipress®,Vasoflex®, Pressin® or Hypovase®) is a sympatholytic drug used to treathigh blood pressure and anxiety, PTSD, and panic disorder. It is analpha-adrenergic blocker that is specific for the alpha-1 receptors.Combining prazosin with the acamprosate sustained release formulationdescribed herein may enhance its central nervous system (CNS) levelsrelative to its systemic levels, as prazosin is both a substrate of andan inhibitor of the ABCG2 efflux pump, which determines the level ofprazosin in the CNS. The enhanced CNS levels may reduce the hypotensionseen early on in treatment with that prazosin, mitigate prazosin foodeffect, or improve the efficacy of prazosin. In some embodiments,

In some embodiments, the composition of acamprosate described hereinfurther comprises a second-generation neuroleptic, such as lamotrigine,quetiapine, neuroleptic.

In some embodiments, the combination is in a single composition, forexample, a bilaycr composition wherein each layer comprising onemedication.

The unit dose or the pharmaceutical composition can be prepared bymethods known in the art, such as via melt pelletization,melt-granulation, or melt-extrusion techniques.

The unit dose or the pharmaceutical composition may further comprise acoating. Many coatings for tablets are generally known in the art, andany suitable coating can be utilized.

The unit dose or the pharmaceutical composition as described herein mayoptionally be coated with one or more coatings. In some embodiments, thesustained release formulation described herein that further comprises asecond medication may contain a coating that freely allows the passageof acamprosate but would limit and control the release of the secondmedication. For instance, a coating can be added that provides foreither pH-dependent or pH-independent release of the second medication,e.g., when exposed to gastrointestinal fluid. When a pH-independentcoating is desired, the coating is designed to help achieving optimalrelease regardless of pH-changes in the environmental fluid, e.g., theGI tract.

Cellulosic materials and polymers, including alkylcelluloses, aresustained release materials well suited for coating the substrates,e.g., pills, tablets, etc.

In other embodiments, the coating can include a pharmaceuticallyacceptable acrylic polymer.

Kits

In another aspect, provided is a kit comprising a composition comprisingacamprosate calcium or another pharmaceutically acceptable salt ofacamprosate described herein and a label instruction of administeringthe composition with or without food.

In another aspect, provided is a kit comprising a composition comprisingacamprosate calcium or another pharmaceutically acceptable salt ofacamprosate described herein and a pharmaceutical composition of asecond medication. In some embodiments, the kit further comprises alabel instruction of administering the compositions together. In someembodiments, the kit further comprises a label instruction ofadministering the composition comprising a composition comprisingacamprosate calcium or another pharmaceutically acceptable salt ofacamprosate with or without food. In some embodiments, the kit furthercomprises a label instruction of administering the compositioncomprising acamprosate calcium or another pharmaceutically acceptablesalt of acamprosate with food if the second medication is to beadministered with food. In some embodiments, the kit further comprises alabel instruction of administering the composition comprisingacamprosate calcium or another pharmaceutically acceptable salt ofacamprosate without food if die second medication is to be administeredwithout food. In some embodiments, the kit is a blister pack comprisinga unit dose of the acamprosate composition and an associated dose of thecomposition of the second medication. Such a package is contemplated tofacilitate optimization of the dose of the second medication.

In some embodiments, the second medication is prazosin.

In some embodiments, the second medication is one or more antipsychotic(neuroleptic) medications, such as first or a second generationantipsychotic. First generation antipsychotic include: chlorpromazine,chlorprothixene, levomepromazine, mesoridazine, periciazine,thioridazine, loxapine, molindone, perphenazine, thiothixene,droperidol, flupentixol, fluphenazine, haloperidol, pimozide,prochlorperazine, trifluoperazine, and zuclopenthixol. Second generationantipsychotic include amisulpride, aripiprazole, asenapine, blonanserin,clozapine, iloperidone, lurasidone, melperone, olanzapine, paliperidone,quetiapine, risperidone, sertindole, sulpiride, ziprasidone, andzotepine.

In some embodiments, the second medication is one or more selectiveserotonin reuptake inhibitors (SSRI), such as citalopram, escitalopram,fluoxetine, fluvoxamine, paroxetine and sertraline.

In some embodiments, the second medication is one or moreserotonin-norepinephrine reuptake inhibitors (SNRI), such as bicifadine,desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramineand venlafaxine.

In some embodiments, the composition of acamprosate described hereinfurther comprises a second-generation neuroleptic, such as lamotrigine,quetiapine, neuroleptic.

In some embodiments, the above described kits further comprise a labelinstruction of administering the composition comprising acamprosatecalcium or another pharmaceutically acceptable salt of acamprosateaccording to any dosage amount or dosing regimens described herein.

Methods of Treatment

In another aspect, provided arc methods of treating a disease, disorder,symptom, or syndrome, such as a neuropsychiatric disorder, in a patientin need of such treatment comprising administering to said patient acomposition or a unit dose of a composition described herein.

Exemplary diseases or disorders include tardive dyskinesia (TD), tardivedystonia, tardive akathisia, dystonia, blepharospasm, levodopa-induceddyskinesia (LID) in patients with Parkinson's disease, simple tics,Tourette Syndrome (TS), obsessive-compulsive disorder (OCD),posttraumatic stress disorder (PTSD), symptoms of schizophrenia,depression, bipolar disorder, autism spectrum disorders, autisticsymptoms in Fragile X syndrome, alcoholism, tinnitus, and generalizedanxiety disorder, and repetitive and stereotypic self-injuriousbehaviors (SIB) in persons with developmental disabilities such asbiting, skin-picking, hitting oneself, and head-banging. In someembodiments, the method is for reducing anxiety and/or agitation in apatient receiving a neuroleptic, anxiety or antidepressant medication.In some embodiments, the method is for treating alcohol dependence.

In some embodiments the methods can include reducing the severity of orreducing or delaying the onset of a disease, disorder, symptom orsyndrome. In some embodiments, the methods can include treating orselecting a particular patient, group or population of patient toreceive treatment. For example, in some embodiments the methods cantreat or select a patient in need of taking acamprosate or anothermedication described herein with food, without food, in a fed or in afasted stated. The patient, group or population can be for example, onethat is susceptible or needs to avoid GI side effects of acamprosate orthe other medication, that needs to take a combination medication withor without food, and therefore desires to take the acamprosate or othermedication in the same manner. In some embodiments the patient, group orpopulation can be one that needs to minimize the number of pills takenper day or needs to take less than 2000 mg, 1500 mg or less ofacamprosate daily with 2 or 3 total pills or less. In some cases, thepatient, group or population can be those susceptible to non-compliancewith an acamprosate or other treatment regimens or that need a regimenthat requires fewer pills or side effects in order to encourage orfacilitate compliance. In still other embodiments, the patient, group orpopulation can include patients that need to avoid or delay the onset ofside effects of a neuroleptic treatment, such as the onset of TD. Insome other embodiments, the patient, group or population can includepatients that experience anxiety or depression, and/or are taking amedication for anxiety or depression and need to treat a condition suchas TD.

TD is a chronic disorder of the nervous system, characterized byinvoluntary, irregularly rhythmic movements most often involving themouth, tongue, and facial muscles. Choreatic or dystonic movements ofthe extremities can be included, as can dystonic movements of the neckor trunk, and rocking movements of the trunk. TD with prominent limb andtrunk movements eis especially disabling and difficult to treat. TD canbe accompanied by tardive akathisia, an irresistible impulse to movewhich is often manifest as continual restless movements of the legs.Another potential accompaniment of TD is disruption of respiratorymovements leading to irregular breathing and subjective shortness ofbreath—respiratory dyskinesia. Most cases of TD are caused by long-termuse of neuroleptics (antipsychotic drugs); the remainder are caused bychronic use of dopamine blocking drugs such as metoclopramide orprochlorperazine that are given to relieve or to prevent nausea andvomiting or, in the case of metoclopramide, to treat diabeticgastroparesis. While most cases arise after months or years of exposureto the causative agent(s), there are numerous well-documented cases inwhich those drugs have induced TD after only a few weeks of exposure.Unlike many drug side effects, tardive dyskinesia usually worsens whenthe causative drug is discontinued, and the condition can persist formonths, years, or even permanently afterwards. The prevalence of tardivedyskinesia with long-term treatment with first-generation antipsychoticdrugs is over 25%, and even higher in elderly patients. While tardivedyskinesia occurs at a significantly lower rate with second-generationantipsychotic drugs, all of them except for clozapine are known to causeTD in some patients.

Additional diseases or disorders that can be treated with acamprosate orthe composition described herein include dyskinetic movements in Rett'sSyndrome, dyskinetic movements in the DiGeorge Syndrome, dyskineticmovements and dystonia in Wilson's disease and post-hypoxic myoclonus.It is contemplated that in some cases treatment of these disorders mayrequire a higher acamprosate plasma concentration than that for treatingTD. The ability of the composition described herein to provide highacamprosate plasma concentrations for at least a number of hours duringa 24 hour period in combination with high tolerability for high doseacamprosate administered with or without food would enable the treatmentof these disorders.

In some embodiments, the composition can be administered once, twice orthree times daily. In some embodiments, the methods can include, forexample, administering to a patient in need thereof a total daily dosageof acamprosate of from 500 mg to 4000 mg per day. In some embodiments,the methods may include, for example, administering to the patientacamprosate at a daily dosage of 1000 mg to 1500 mg, or 1300 mg to 1500mg, or more, on a once-a-day schedule with or without food (in a fed ora fasted state). In some embodiments, the methods may include, forexample, administering to the patient acamprosate at a daily dosage of1000 mg to 1500 mg, or 1300 mg to 1500 mg, or more, on a twice-a-dayschedule with or without food (fed or fasted). In some embodiments, themethods may include, for example, administering to the patientacamprosate at a daily dosage of 800 mg to 1500 mg (or any value orrange there between, end points inclusive, such as 1300 mg to 1500 mg)once a day with or without food (fed or fasted). In some embodiments,the methods may include, for example, administering to the patient about4000 mg of acamprosate per day. In some embodiments, the methods mayinclude, for example, administering to the patient acamprosate in twotablets twice a day wherein each tablet comprises 800 mg to 1000 mg, ofacamprosate. In some embodiments, the methods may include, for example,administering to the patient acamprosate in one tablet three times a daywherein each tablet comprises 1300 mg to 1400 mg of acamprosate. In someembodiments, the methods can include, for example, administering to thepatient acamprosate in two tablets once a day, such as in the morning,and one tablet once a day, such as in the evening or about 10-14 hoursbefore or after administration of the two tablets, wherein each tabletcomprises 1300 mg to 1400 mg of acamprosate. The once or twice dailyacamprosate administration respectively can be a dosage of 1000 mg, lessthan 1000 mg, more than 1000 mg, or equal to or less than 1400 mg, forexample, in a dosage of 200 mg to 450 mg, or 350 mg to 900 mg, or 900 mgto 1400 mg. The administration of acamprosate is tolerated whetheradministered with or without food.

Without being limited thereto, when administered, the acamprosate can beadministered as one, two or three units of a dosage form, for example,one, two or three pills or tablets. The single unit of a dosage form orthe multiple units of a dosage form can have, for example, a totalweight of up to 1500 mg, such as less than 1200 mg. For example, in someembodiments herein, the total unit dosage form weight can be between 400and 1500 mg, between 500 and 1200 mg, between 600 and 1200 mg, or anyvalue or sub range within those ranges. TABLE 1 below providesnon-limiting dosing regimens.

In some embodiments, the patient is administered a composition or a unitdose of a composition described herein in a fed or fasted state, and thepatient may choose to take each individual dose on each individualoccasion in either the fed state or the fasting state. In someembodiments, the patient is administered a composition or a unit dose ofa composition described herein in a fasted state. In some embodiments,the patient is administered a composition or a unit dose of acomposition described herein in a fed state. In some embodiments, themethods specifically can exclude administration in the fasted or the fedstate. In some embodiments, the patient is administered a composition ora unit dose of a composition described herein immediately prior to foodintake (e.g., within 30 minutes or within 60 minutes of taking food),with food, or soon after food intake (e.g., within 30 minutes, within 60minutes or within 2 hours of food intake). In some embodiments thepatient is administered a composition or a unit dose of a compositiondescribed herein without food, for example, after an overnight fast, ornot less than 30-60 minutes prior to a meal or not less than 1 hour, 2hours, three hours after a meal, or more. In some embodiments, thepatient is administered a composition or a unit dose of a compositiondescribed herein at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or moreafter food intake, or any time there between. In some embodiments, thepatient is administered a composition or a unit dose of a compositiondescribed herein at least 30 minutes before food intake, at least 1hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours or more before food intake, or anytime there between.

In some embodiments, acamprosate is administered once or twice daily,for example, to achieve the total daily dosage, and the administeredacamprosate can be in a composition that is formulated to release atleast 50% of the acamprosate over a 2-8 hour period or any sub value orsub range there between. In some aspects, at least 50% is releasedwithin the first 4 hours. In some aspects, at least 90% is released fromthe composition within 8 hours.

In some embodiments, when the composition is given TID, it can be takenfor example with food for one or two doses and without food for one ortwo doses.—This is made feasible by the fed-fasting equivalence. In someembodiments, when a patient is already taking other medications doses ofthe acamprosate formulation provided herein can be taken in conjunctionwith other medications, favoring compliance. It is noted that mostpatients with neuropsychiatric disorders will be on other medications.In some embodiments, a patient tolerates the formulation provided hereinbetter with food—or better without food and the formulation can be takenin any suitable manner without any concern of the difference intherapeutic effect.

Pharmacokinetics and Compositions and Methods Related Thereto

Some embodiments herein are related to methods and compositions wherethe pharmacokinetics (PK) of acamprosate are altered.

It was surprisingly found that the compositions described herein canexhibit substantially the same PK profile when administered to a patientin a fed state or in a fasted state. The effect of food to reduceacamprosate absorption did not occur. For example, a formulationcomprising 800 mg of acamprosate exhibited substantially the same PKprofile in the fed and fasted states. The compositions according to atleast some embodiments can release acamprosate by diffusion,substantially proportionally to the square root of time in vitro, andcan maintain their integrity in the GI tract for several hours whenadministered in a fed state or in the fasted state. Also, more than 50%of the drug can be released within, for example, about 3-5 hours. Stillfurther, unexpectedly and surprisingly it was found that even throughthe amount of acamprosate is much higher than two Campral® tablets eachcomprising 333 mg of acamprosate calcium, the formulation comprising 800mg or more of acamprosate calcium was well-tolerated in humans in bothin a fed state and in a fasted state, with only one subject (8.3% of a12-subject sample) reporting any GI side effect (diarrhea) in the fastedstate, and no subject reporting any GI side effect in the fed state. Thedata indicate that the compositions of the instant technology (e.g.,those comprising 800 mg to 1500 mg acamprosate) are more tolerable thanCampral® from the GI standpoint, especially because patients will havethe option of taking the drug with food (in a fed state) if they have GIside effects in the fasted state, as there are no food effects on PK.

Immediate-release (IR) acamprosate (which is equivalent to acamprosatesolution because acamprosate is immediately and completely soluble ingastric juice) has twice the bioavailability of enteric-coatedacamprosate (Saivin S et al., Clinical Pharmacokinetics of Acamprosate,Clinical Pharmacokinetics Vol. 35, Number 5, November 1998, pp. 331-345,which is incorporated herein by reference in its entirety). However, IRacamprosate has a PK profile characterized by a relatively high andearly Cmax and a relatively rapid decline in plasma concentration afterCmax is attained. without wishing to be bound by any theories, it iscontemplated that the therapeutic efficacy of acamprosate probably isbased on maintaining the acamprosate plasma level above a thresholdconcentration for a minimum number of hours per day. For example,efficacy might require a residence time of 6 hours above 200 ng/mL for asingle dose. The dosage of IR acamprosate needed to produce thisresidence time would be associated with a higher Cmax with than the doseof the formulation described herein needed to produce this residencetime. IR acamprosate would thus have two reasons to produce more GI sideeffects than the formulation described herein—a higher localconcentration of acamprosate in the stomach, and a higher maximum plasmaconcentration.

Campral® tablets have a Tmax of over 8 hours and a dose-normalized Cmaxwell below that of the present formulations; their PK curve isrelatively flat. Adding to the shape of the PK curve consideration ofthe food effect on absorption, to consistently attain an above-thresholdresidence time (for the acamprosate plasma level) of six or eight hoursa day using Campral® will usually require attaining a level near orabove the threshold for 24 hours a day. Considering this point and thefood effect one can conclude that the total daily dosage of theacamprosate formulations described herein required for therapeuticefficacy for a given condition may be substantially lower than the totaldaily dosage of Campral® that would be required for the same therapeuticefficacy. Therefore the formulations described herein may be efficaciousfor neuropsychiatric indications at dosages and on dosing regimens thatare better tolerated and more conducive to long-term treatment adherencethan the ones that would be necessary using Campral®.

For the just-noted reasons the sustained release formulations describedherein may be efficacious at total daily doses of less than 1 gram perday, and when they are and these formulations could be given on atwice-daily schedule, and even on a once-daily schedule, depending onthe threshold plasma level and daily time above that level required forefficacy in a given patient. Depending on the indication, the minimumnumber of hours a day the acamprosate plasma level that must be above athreshold to attain therapeutic efficacy might be four, six, or eighthours, or some other number of hours. However it is very unlikely thatthe plasma level for therapeutic efficacy would need to be maintainedcontinuously over 24 hours for any indication, because the mechanism ofaction of acamprosate is via inducing the alteration of glutamatereceptor composition and conformation, and not via the ongoing occupancyof glutamate receptor sites. The model system studied was based onsustained release over eight hours. In some embodiments, it is evidentthat sustained release over six hours or sustained release over fourhours can be satisfactory for therapeutic advantage, depending on thetime and concentration thresholds for efficacy in particular patientpopulations and for particular indications. The following TABLE 1illustrates example dosing regimens.

TABLE 1 Total daily dosage Dosage per tablet Dosing schedule  1.5 grams 1.5 grams 1 tablet once a day  3 grams  1.5 grams 1 tablet twice a day 4.5 grams  1.5 grams 2 tablets in the morning and 1 tablet in theevening  1 gram  1 gram 1 tablet once a day  2 grams  1 gram 1 tablettwice a day  4 grams  1 gram 2 tablets twice a day 800 mg 800 mg 1tablet once a day  1.6 grams 800 mg 1 tablet twice a day  3.2 gram 800mg 2 tablets twice a day 400 mg 400 mg 1 tablet once a day 800 mg 400 mg1 tablet twice a day  1.6 grams 400 mg 2 tablets twice a day

Enteric-coated acamprosate is only half as bioavailable as IRacamprosate and has a lower maximum concentration (C_(max)) and longertime to peak concentration (T_(max)) than IR acamprosate. The sustainedrelease acamprosate formulation provided herein has an even greatertherapeutic advantage over enteric-coated acamprosate than over IRacamprosate. Furthermore, the steady-state concentration in the plasmawhen enteric-coated acamprosate is given three times a day is approachedslowly over 5-7 days, with the plasma level of acamprosate during thefirst several days of administration below the eventual steady-stateplasma level. By contrast, a sustained release formulation ofacamprosate given in the fed or fasted state according to embodimentsdescribed herein that provides sustained delivery of acamprosate where asingle dose can reach the plasma level of acamprosate attained onlyafter several days on the enteric-coated version, and it can maintainthat level for a number of hours sufficient for efficacy although insome cases the level is not maintained for the entire 24-hour period. Insome embodiments, it is believed that the therapeutic efficacy of anacamprosate formulation depends upon its producing plasma levels above athreshold for a minimum number of hours per 24-hour day—but not all 24hours necessarily. Not wishing to be bound by any theory, it iscontemplated that this is because the mechanism of action of acamprosatein the brain is based on synthesis of proteins that persist for manyhours after they are synthesized. Further, clinical observations ofCampral® treatment suggest that unevenly distributed TID dosing can givebetter therapeutic results than evenly distributed TID dosing, which mayproduce a low, flat PK curve. That at steady state one would be eitherabove threshold all the time or below it all the time. Thus a high dailydosage of Campral® is needed in order that the steady state is above thethreshold. While the IR acamprosate would provide high plasma level forat least a number of hours, there would be a tolerability concernrelated to high local concentrations in the stomach and a high C_(max)in the plasma. The novel SR formulations described herein provide forseveral hours above a potential therapeutic threshold after eachdose—without attaining the high C_(max) that would be needed to get thesame residence time with an IR preparation, and without having the highlocal gastric concentration of drug one would have with an IRpreparation.

Thus, consistent with the human case set forth in EXAMPLE 1 thatevidences that there is a therapeutic threshold that needs to beexceeded for significantly less than 24 hours, for example, six or eighthours per 24 hours, the dosing of 400 mg of sustained releaseacamprosate twice a day, or possibly 800 mg once a day, can be effectivein some embodiments. This supports efficacy in some cases for thesustained release formulation at a total daily dose of less than 1000 mgper day—less than the previously recognized therapeutic range and notexplained by mere bioequivalence with some dose in the previouslyrecognized therapeutic range. Because this lower dose of the SRpreparation would not have a greater AUC than the same dose of Campral®,its efficacy is not expected from the prior art, which does notexplicitly include alternate formulations of acamprosate that producethe same concentrations of acamprosate in blood and/or brain as thoseproduced by doses of 1 gram to 2.6 grams of Campral®, the onlyformulation available at the time the prior art was published.

Further, it should be understood that according to some embodiments thesub gram, twice or once a day regimens (e.g., 400 mg twice a day or 800mg once a day regimens) of sustained release acamprosate do not giveequivalent concentrations in the plasma to those produced byenteric-coated acamprosate given in a higher total daily dose on a threetimes daily schedule. The latter would give—after 5-7 days—a stablelevel of acamprosate, whereas the sustained release regimens describedherein can produce a fluctuating level of acamprosate that might bebelow the steady state level for enteric-coated acamprosate, at sometimes of the day. Thus, the sustained release formulations given at lessthan 1 grain per day would not be bio-equivalent to the enteric-coatedformulation given at dosages of 1 gram to 2.6 grams on a three times aday schedule, and in fact, in some embodiments, it would usually have a24-hour AUC in less than that produced by Campral® given on a typicalTID schedule (e.g., 333 mg TID). For these reasons the use of sustainedrelease acamprosate at a daily dose of less than 1 gram per day given ona once-daily or twice-daily basis in the fed or fasted state is notsuggested by the prior art, and its (expected) efficacy for TD (and forother neuropsychiatric disorders) is a novel and unexpected discovery.

The sustained release acamprosate formulations (e.g., tablets) accordingto some embodiments herein can thus be of size such that the totaltablet or pill is easy to swallow. For example, the specificallydescribed formulations herein, in particular, 400 mg sustained releaseacamprosate tablets, 800 mg, and even up to 1500 mg sustained releaseacamprosate tablets are small enough to be easily swallowed. They thusmake possible reasonably-sized fixed-dose combination tablets comprisingsustained release acamprosate and another drug that is given in asubstantially lower dosage than the sustained release acamprosate,typically at a dosage of less than 200 mg per day.

In some embodiments, provided is a way to administer a therapeuticdosage of acamprosate in one (relatively) small dose that only has to betaken once or twice daily. The smaller dosage form also can haveancillary benefits. First of all, the smaller dosage can lead to lesserside-effects. It also can lead to improved patient compliance due tobeing taken fewer times each day, for example, once daily. Additionally,smaller dosage forms allow for more convenient co-administration ofacamprosate with other drugs, for example as part of a single dosageform or as separate dosage forms.

In some embodiments, administration of a composition or a unit dose of acomposition described herein provides a plasma concentration having anarea under curve (AUC) at 8 hours after administration that is at least33% of the AUC at 48 hours after administration.

In some embodiments, administration of a composition or a unit dose of acomposition described herein to a patient provides substantially thesame PK profile in said patient whether it is administered in a fedstate or in a fasted state. In some embodiments, the pharmacokineticprofiles in a fed state and in a fasted state are consideredbioequivalent by a regulatory agency, such as the U.S. Food and DrugAdministration (e.g. 80-125% of a reference product). In someembodiments, administration of the composition or unit dose to thepatient results in a 90% confidence interval (CI) for acamprosate plasmaC_(max) in the fed state being 90 to 110% of the C_(max) in the fastedstate. In some embodiments, administration of the composition or unitdose to the patient results in a 95% CI for acamprosate plasma C_(max)in the fed state being 90 to 110% of the C_(max), in the fasted state.In some embodiments, administration of the composition or unit dose tothe patient results in a 90% CI for acamprosate plasma T_(max) in thefed state being 90 to 110% of the T_(max) in the fasted state. In someembodiments, administration of the composition or unit dose to thepatient results in a 95% CT for acamprosate plasma T_(max) in the fedstate being 90 to 110% of the T_(max) in the fasted state. In someembodiments, administration of the composition or unit dose to thepatient results in a 90% CI for acamprosate plasma AUC in the fed statebeing 90 to 110% of the AUC in the fasted state. In some embodiments,administration of the composition or unit dose to the patient results ina 95% CI for acamprosate plasma AUC in the fed stated being 90 to 110%of the AUC in the fasted state. In some embodiments, administration ofthe composition or unit dose to the patient results in two or more ofthe above. In some embodiments, administration of the composition to thepatient results in all of the above.

In some embodiments, the methods can include, for example, administeringan acamprosate dosage form once or twice per day to a patient in a fedstate wherein the dosage form comprises up to 4 grams of acamprosate forexample, and a total dosage of from 1 gram to 4 grams of acamprosate,per day. In some embodiments, such a dosage form is retained uponadministration in a fed state in the stomach of the patient for at least4 hours. In some embodiments, the methods can include comprisesadministering an acamprosate dosage form once or twice per day to apatient in a fasted state wherein the dosage form comprises up to 4grams of acamprosate, for example, from 1 gram to 4 grams ofacamprosate, per day, which dosage form upon administration is retainedin the stomach of the patient for no more than one hour whenadministered in a fasted state. In some embodiments, each unit of thedosage form comprises about 800 mg of acamprosate, and is administeredonce, twice or three times daily, and when administered once or twicedaily, one unit or two units of the dosage form can be administered. Insome embodiments, each unit of the dosage form comprises about 1300 mgof acamprosate, and is administered once, twice or three times daily,and when administered once or twice daily, one unit or two units of thedosage form can be administered. In some embodiments, the method is fortreating tardive dyskinesia.

In some embodiments, provided are compositions for and methods ofmaintaining an in vivo steady-state acamprosate plasma concentration forat least 4-8 hours, preferably about 6 hours, out of a 24 hour period ator above a minimum level needed for therapeutic efficacy for treating aneuropsychiatric or other medical condition in a patient in needthereof. The method may include, for example, administering to thepatient a dosage of a pharmaceutically acceptable salt of acamprosate,wherein the dosage form comprises up to 1.5 grams of acamprosateformulated in a polymer matrix that releases acamprosate by diffusion,and the dosage is administered either once daily or twice daily. In someembodiments, the dosage form may include less than 1 gram ofacamprosate.

It surprisingly has been discovered that in some embodiments acamprosatetreatment can be efficacious even though the acamprosate concentrationdoes not exceed the threshold for the entire 24 hour period or eventhough the concentration or levels of acamprosate are very inconsistent(not at steady levels) during a given period of time such as a 24 hourperiod. The methods described herein where several hours ofexposure—typically between 4 and 8 hours—to an adequate level ofacamprosate can produce therapeutic effects on CNS function lasting forhours after the level of acamprosate falls—and often for the remainderof a 24 hour day. Thus, a single dose of an acamprosate compositiondesigned to release the drug over a 4-8 hour period, such as thosedescribed herein, can be sufficient to give a 24 hour therapeuticeffect.

It has been discovered that the shape of the PK curve and not just theAUC can make a difference to efficacy. Specifically, having a plasmaconcentration above a threshold for several hours per day (e.g., 4-8hours) may be more efficacious than maintaining a concentration justbelow that threshold for 24 hours a day. In a simulated dog model of asustained release it was shown that sustained presentation ofacamprosate over eight hours yielded a significantly longer residencetime above a threshold concentration than immediate release of the samedosage, even when there was not a significant difference in the AUG. Inthis model, the drug conserved by avoiding a high single dose and highC_(max), was distributed across several hours, giving a several hourperiod in which the plasma concentration of acamprosate was higher thanthe plasma concentration after administration of a single dose of theimmediate release version.

Immediate release formulation was found to release acamprosate in astrict dose linearity of AUC and C_(max) with oral dosing between 333and 2664 mg, albeit with 6 subjects. Saivin S, Hulot T, Chabac S, etal.: Clinical pharmacokinetics of acamprosate. Clinical Pharmacokinetics35(5): 331-345, 1998.

Further, clinical observations of TD cases were made showing thatenteric coated acamprosate (Campral®) given three times daily hadgreater efficacy lower daily dosage when the daily dosage was dividedunevenly among the three doses, even when the total number of pillsadministered per 24 hours in less in the uneven schedule than the normalschedule. Not wishing to be limited by any theory, it is noted that thetherapeutic action of acamprosate in TD is based on its effects onglutamate transmission. These effects are not based on directinteraction of acamprosate with glutamate receptors, but rather ondownstream effects of acamprosate modulation at other sites on theneuron. Reilly M T, Lobo I A, McCracken L M, et al.: Effects ofacamprosate on neuronal receptors and ion channels expressed in XenopusOocytes. Alcoholism Clinical and Experimental Research 32(2): 188-196,2008. These downstream effects are based in part on modulation ofprotein synthesis, a mechanism implying the potential for persistence ofeffect after the drug is no longer present at a threshold level forclinical efficacy.

In some embodiments, the pharmaceutically acceptable salt of acamprosateis formulated in a polymer matrix that releases, by diffusion in vitro,approximately 50% of the acamprosate within 2 hours and releases atleast 80% of the acamprosate within 4-6 hours.

In some embodiments, the steady-state in vivo acamprosate plasmaconcentration is maintained at or above a threshold for therapeuticefficacy for at least 6 hours out of a 24 hour period, wherein thetherapeutic threshold is about 100 ng/mL, 150 ng/mL, 200 ng/mL, 250ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, or 500 ng/mL, or anyranges between any two of the numbers (end points inclusive).

In some embodiments a formulation of acamprosate which can provide ahigher C_(max) and shorter T_(max) than Campral® for an equal dose willbe efficacious at a lower total daily dose, where sustained absorptionleads to attaining a therapeutic threshold for a sufficient number ofhours a day. In some embodiments, the therapeutic threshold is a plasmalevel of not higher than 1000 ng/mL and generally not less than 100ng/mL (or any value or range there between, the endpoints inclusive). Insome embodiments, the therapeutic threshold is a plasma level of nothigher than 500 ng/mL and generally not less than 200 ng/mL. In someembodiments, a plasma level of at least 150 ng/mL or at least 200 ng/mLis attained for at least 6 hours, 7 hours, or 8 hours, or any rangesbetween any two of the values, end points inclusive. In someembodiments, a plasma level of at least 100 ng/mL or at least 200 ng/mLis attained within one hour after administration. In some embodiments,T_(max) is attained in 1 to 5 hours or 2 to 5 hours.

In another aspect, provided herein is a composition comprisingacamprosate, having one or more of the following in vitro dissolutionproperties:

-   -   1) remaining substantially intact for at least 4-12 hours at pH        1.0 or at pH 4.5 or a pH between about 1.0 and about 4.5, (e.g.,        the composition stays firm or very firm and elastic or can be        picked up with slight resistance and does not disintegrate;        however, the composition can swell to a bigger size, such as        some or all dimensions are from about 100 ( )0 to 200% of the        original),    -   2) dimensions of the composition are within 80% to 200% of the        original dimensions),    -   3) releasing acamprosate by diffusion at a rate substantially        proportional to the square root of time, (e.g., the average        release rate of acamprosate from the formulation is within 80%        to 120 % of the rate that is proportional to the square root of        time),    -   4) releasing more than 50% of acamprosate within 4 hours and        approximately 80% of acamprosate at 6 hours,    -   5) having substantially equivalent in vitro acamprosate        releasing profiles at pH 1.0 and pH 4.5,    -   6) comprising at least 400 mg of acamprosate, and    -   7) having a minimum length along at least one axis of 10 mm and        a maximum length on at least one axis of 30 mm, such as each        dimension is independently selected from 12 mm, 15 mm, 20 mm, 25        mm, or any value or sub-range there between.

In some embodiments, the in vitro release profile at pH 1.0 can bedetermined by placing a composition described herein in a vessel filledwith a 1M HCl aqueous solution, for example, by following the proceduredescribed in EXAMPLE 4. In some embodiments, the in vitro releaseprofile at pH 4.5 can be determined by placing a composition describedherein in a vessel filled with an aqueous acetate solution, for example,by following the procedure described in EXAMPLE 4.

In some embodiments, the composition can include, for example,acamprosate calcium or another pharmaceutically acceptable salt ofacamprosate, and a high molecular weight polymer, including for example,those capable of forming a hydrogel matrix when contacting water, suchas a PAA or carbomer described herein, polyox (polychtylenc oxide), HPMC(hydroxypropylmethuycellulose), PVA (polyvinyl alcohol), PA (polyacrylicacid) and its derivatives, Xanthan gum, metolose (cellulose derivative),and poly (2-hydroxy-methyl)methacrylate. In some embodiments, thepolymer is able to provide a sufficient hardness and low friability overa wide range of compression forces and form a matrix (e.g., a hydrogelmatrix) when contacting water such that the composition retains itsintegrity in a solution and in the GI tract. In some embodiments, thepolymer is present in the composition at from about 1% to about 25% ofthe total weight of the composition, such as about 1%, about 2%, about3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about23%, about 24%, or about 25% of the total weight of the composition, orany value or ranges between any two of the numbers (end pointsinclusive). The compositions can include a dosage of acamprosate as setforth herein, for example. The compositions can release the acamprosateaccording to the profiles described herein, and/or can provide a pKprofile (one or more of the parameters herein) that is within 80%-120%of the profiles of one or more of the formulations of Example 3. Thus,one or more of the excipients described above can be substituted for orincluded with the carbomers described herein to provide formulationswith substantially the same properties. Such formulations also can betaken in a fed or fasted stated, with or without food as desired, andcan be combined with the other medications as described herein.

In some embodiments, provided herein is a composition comprisingacamprosate, wherein when administered to a human in a fed state thecomposition is retained in the stomach for at least 3-4 hours.

In some embodiments, provided herein is a composition comprisingacamprosate, wherein when administered to a human in a fasted state thecomposition is retained in the stomach for no more than three hours,such as no more than two hours, or no more than one hour.

In some embodiments, provided herein is a composition comprisingacamprosate, wherein when administered to a human in a fed state or in afasted state the composition is substantially intact when it reaches thecolon.

In some embodiments provided is a composition that is retained in thestomach for more than 3-4 hours (such as at least 5 hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours, or any rangewithin any two of the values, end points inclusive) when given in thefed state, thus releasing most of acamprosate in the stomach and thusexposing most of the released acamprosate to the entire small intestinalsurface, thereby maximizing absorption via diffusion. In someembodiments, the composition is in the jejunum within 3 hours (or 2.5hours, 2.25 hours, 2 hours, 1.5 hours, 1 hour, or 30 minutes, or anyrange within any two of the values, end points inclusive) whenadministered to a patient in a fasted state, thus most of the drug isreleased more distally, and does not compete with food for absorption.In some embodiments, the location of the composition does notsubstantially affect the release rate of acamprosate. Without beingbound to any theory, it is believed that these surprising behaviors ofthe composition provides balance of many different factors influencingrelease and absorption of acamprosate, such that the AUC and C_(max) ofplasma levels are substantially the same when the composition isadministered to the subject in the fed state and when the composition isadministered to the subject the fasted state.

In some embodiments, the composition comprises 700 mg to 1500 mgacamprosate in each unit that is formulated so that the composition isretained in the stomach for at least 4 hours when administered to apatient in a fed state. In some embodiments, the composition comprises700 mg to 1500 mg acamprosate in each unit that is formulated so thatthe composition is retained in the stomach for no more than 3 hours orno more than 1 hour when administered to a patient in a fasted state.

In some embodiments, provided herewith is a composition comprising apharmaceutically acceptable salt of acamprosate, such as acamprosatecalcium, wherein when administered to a human releases acamprosate atsubstantially the same rate in vivo as it does in vitro.

In another aspect, provided herein is a composition comprising apharmaceutically acceptable salt of acamprosate, such as acamprosatecalcium, wherein when administered to a human said composition producesa plasma concentration of acamprosate characterized by one or more ofthe following:

-   -   1) The 8-hour AUC is on average at least one-third of the        48-hour AUC;    -   2) The 12-hour AUC is on average at least one-half of the        48-hour AUC.    -   3) The average C_(max) is less than about 500 ng/ml after a        single unit of the composition comprising up to about 800 mg of        a pharmaceutically acceptable salt of acamprosate, such as        acamprosate calcium, is administered,    -   4) The average C_(max) is less than about 750 ng/ml after a        single unit of the composition comprising up to about 1200 mg of        a pharmaceutically acceptable salt of acamprosate, such as        acamprosate calcium, is administered,    -   5) The average AUC and C_(max) arc substantially the same when        the composition is administered to humans in the fed state and        when the composition is administered to humans in the fasted        state.

In some embodiments, the composition comprises acamprosate calcium oranother pharmaceutically acceptable salt of acamprosate and a highmolecular weight polymer, such as a PAA or carbomer described herein,polyox (polyehtylene oxide), HPMC (hydroxypropylmethuycellulose), PVA(polyvinyl alcohol), PA (polyacrylic acid) and its derivatives, Xanthangum, metolose (cellulose derivative), and poly(2-hydroxy-methyl)methacrylate. In some embodiments, the polymer is ableto provide a sufficient hardness and low friability over a wide range ofcompression forces and form a hydrogel matrix when contacting water suchthat the composition retains its integrity in a solution and in the GItract. In some embodiments, the polymer is present in the composition atfrom about 1% to about 25% of the total weight of the composition, suchas about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,about 21%, about 22%, about 23%, about 24%, or about 25% of the totalweight of the composition, or any value or ranges between any two of thenumbers (end points inclusive). The compositions can include a dosage ofacamprosate as set forth herein, for example. The compositions canrelease the acamprosate according to the profiles described herein,and/or can provide a pK profile (one or more of the parameters herein)that is within 80%-120% of the profiles of one or more of theformulations of Example 3. Thus, one or more of the excipients describedabove can be substituted for or included with the carbomers describedherein to provide formulations with substantially the same properties.Such formulations also can be taken in a fed or fasted stated, with orwithout food as desired, and can be combined with the other medicationsas described herein.

In some embodiments, provided herein is a composition comprising apharmaceutically acceptable salt of acamprosate, such as acamprosatecalcium, wherein when administered to a human the formulation iswell-tolerated whether administered with or without food. In someembodiments, the composition is well tolerated even when administered ata dosage of up to 4 grams per day. In some embodiments, a 3 to 4 gramdaily dose can be administered in two tablets twice a day (BID) whereineach tablet comprises 750 to 1000 mg of acamprosate. In someembodiments, a 4 gram dose can be administered in one tablet three timesa day (TID) wherein each tablet comprises 1300 mg to 1400 mg ofacamprosate. In some embodiments, a 2.6 gram dose can be administered intwo tablets once a day, such as in the morning, or two tablets once aday, such as in the evening, wherein each tablet comprises 1300 ofacamprosate.

In some embodiments, provided herein are methods of treating aneuropsychiatric disorder that can include for example administering acomposition comprising up to 1500 mg of a pharmaceutically acceptablesalt of acamprosate, such as acamprosate calcium, once or twice a day.In some embodiments, the composition comprising less than 1 gram, suchas 800 mg of a pharmaceutically acceptable salt of acamprosate, such asacamprosate calcium, is administered once a day. It is surprising that800 mg of acamprosate in the composition administered once a day wouldbe effective in treating a neuropsychiatric disorder as 800 mg is lowerthan the lowest dose of Campral® ever reported to be or claimed to betherapeutically effective for any condition. For example, thecurrently-marketed enteric-coated acamprosate calcium tablets must begiven on a three times daily schedule in doses of 2 grams or more perday to be efficacious in treating alcoholism, and many patients requiremore than 2 grams or more to get relief of symptoms. Similarly, whenused to treat TD and other neuropsychiatric disorders, Campral® has beenused by one of the inventors on an open-label basis at dosages rangingfrom 1 gram to 3.6 grams per day (3 to 11 tablets daily) on athrice-daily schedule. The average minimal dose for obtaining an optimalresponse in treating TD with Campral on an open-label basis has been 3grams daily. Case reports of the use of Campral® for otherneuropsychiatric indications such as tinnitus or autism have always usedno less than 333 mg TID.

Some embodiments relate to methods for reducing or eliminatinggastrointestinal side effects associated with acamprosate treatment,which method comprises administering a acamprosate composition describedherein. It was found that even though the amount of acamprosate calciumin an 800 mg tablet of a formulation described herein is significantlyhigher than that in two Campral® tablets each comprising 333 mg ofacamprosate calcium, the formulation comprising 800 mg or more ofacamprosate calcium was well-tolerated in humans in both in a fed stateand in a fasted state, with only one subject (8.3 % of 12 subjectsreporting any GI side effect (diarrhea) in the fasted state, and nosubjects reporting diarrhea in the fed state, or any other GI sideeffect in either the fed or the fasting state. In some embodiments, themethod comprises administering to a patient in need acamprosatetreatment a total daily dosage of acamprosate of less than 1000 mg,wherein the acamprosate is administered once or twice daily to achievethe total daily dosage, and the administered acamprosate is in acomposition that is formulated to release at least 50% of theacamprosate over a 4-8 hour period. In some aspects, at least 50% isreleased within the first 4 hours. In some aspects, at least 90% isreleased from the composition within 8 hours. The side effect to bereduced or eliminated can be, for example, nausea, diarrhea, dyspepsiaand/or vomiting. In some embodiments, the method comprises administeringan acamprosate composition described herein in a fed state. In someembodiments, the method comprises administering an acamprosatecomposition described herein in a fasting state in which the formulationis retained in the stomach for no more than 1 hour.

In some embodiments the side effect is reduced by administering acomposition described herein, in particular a sustained release versionof acamprosate, as compared with the immediate-release version, sincethe maximum concentration of the drug in the gastric juice or in theintestine, and the maximum concentration in the blood, will be lowerthan with the immediate release version.

The most common side effects of acamprosate that can be reduced oreliminated are gastrointestinal symptoms—including nausea, vomiting,diarrhea, and dyspepsia. For patients with alcoholism these side effectsoften lead to noncompliance, and in turn to decreased effectiveness oftreatment. For patients with TD, who often are so distressed by theirmovements that they will adhere to effective treatment despite sideeffects, the gastrointestinal side effects make treatment unpleasant, orlimit the acamprosate dose to one that does not completely relieve theirinvoluntary movements. For all patient groups taking multiple pillsthree times daily is inconvenient and burdensome. The reduced sideeffects, and/or reduced dosage and administration frequency madepossible by the compositions described herein will improve treatmentcompliance.

Combinations and Related Methods of Treatment

In some embodiments, the methods described herein further comprisesadministering the formulations of acamprosate with one or more othermedications, such as first-generation neuroleptic (antipsychotic) drugs,second generation neuroleptic drugs, selective serotonin reuptakeinhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors(SNRIs), or the anti-nausea drug metoclopramide, such as those describedherein. The oilier medication can be administered with acamprosate in afixed dose form or in separate dosage forms simultaneously orsequentially, such as at a different time, on the same or differentdosing schedule, as long as patient is being treated with bothmedication. For example, the decreased dosage amount and frequency ofdosing made possible by the formulations described herein makes itfeasible to formulate fixed-dose combinations of acamprosate and othermedications, such as first-generation neuroleptic drugs. The fixed dosecombinations with first-generation neuroleptics, for example, canprovide effective treatment of psychosis with a lesser risk of metabolicside effects than seen with second-generation neuroleptic drugs, alesser risk of tardive dyskinesia than seen with first generationneuroleptic drugs given alone, and with, unexpectedly, increased reliefof mental symptoms compared with first-generation neuroleptic drugsgiven alone.

Some embodiments relate to combinations of from 500 mg to 4 grams, or100 mg to less than 1 gram (e.g., 800 mg) of a pharmaceuticallyacceptable salt of acamprosate with a drug from a second class, forexample, where the second drug is given in a dose ranging from half ofthe lower end of its usual dosage range to the upper end of its dosagerange. The combination pill may be given either once or twice a day totreat a neuropsychiatric disorder, for example.

The fixed dose compositions comprising a first or second generationneuroleptic combined with a formulation of acamprosate described hereincan be used to treat any of the disorders treated with, for example,neuroleptic drugs or metoclopramide, including schizophrenia,schizoaffective disorder, bipolar disorder, major depression, delusionaldisorder, organic psychoses, delirious agitation, or nausea andvomiting. They can be given for this purpose on a once-daily ortwice-daily schedule (or more if desired), typically with a single pillor tablet given each time. They can provide for a given dosage ofneuroleptic, equal or greater benefit for the neuropsychiatric disorderor symptoms being treated, and can offer greater relief of anxiety andagitation when these are among the symptoms. Compared with the same doseof a first-generation neuroleptic given without acamprosate, thesecombinations entail a lower risk of tardive dyskinesia and other tardivemovement disorders, and they will cause movement disorder of lesserseverity, if they cause one at all. In contrast with second-generationneuroleptics of equal therapeutic efficacy, these combinations can carrya lesser risk of significant metabolic disturbances including weightgain, glucose intolerance, and increased risk of atheroscleroticcardiovascular disease.

Some embodiments relate to methods of reducing the risk or delaying theonset of tardive dyskinesia comprising administering to a patient inneed thereof a combination as described herein. Some embodiments relateto methods of continuing neuroleptic treatment in a patient who alreadyhas tardive dyskinesia but requires continued neuroleptic therapy for achronic mental disorder; treatment with the combination of acamprosateand the neuroleptic reduces the severity of the TD while providing equalor greater benefit in treating the mental disorder.

In the case of acamprosate combined with a neuroleptic, the combinationmay reduce the risk or delay the onset of tardive dyskinesia (TD)associated with giving the neuroleptic drug. Also, unexpectedly, thecombination has additional benefits for the patient's mental status,such as decreased anxiety and/or agitation (as shown in Example 1 and 2below). If the patient has pre-existing TD associated with cognitiveimpairment the acamprosate may also provide an improvement in cognition.The action of acamprosate to treat—and consequentially to prevent themanifestation of—tardive dyskinesia, combined with the additionalbenefit of improving some mental symptoms—makes higher-potency andfirst-generation neuroleptic drugs more attractive when they are givenin combination with acamprosate. At present the first-generation,high-potency neuroleptic drugs are avoided because they are more likelythan second-generation neuroleptic drugs to produce tardive dyskinesia.However, those drugs are no less efficacious in treating psychosis thanthe second-generation drugs (with the sole exception of clozapine), andsecond-generation drugs usually are more expensive, and have seriousmetabolic effects with potentially life-threatening consequences. It isrational to combine even second-generation neuroleptics withacamprosate, because those drugs still carry some risk of TD, and theadditional psychiatric benefit can still apply. TABLES 11 and 12 belowshow non-limiting examples of the dose ranges for the neuroleptic drugsand the sustained-release acamprosate formulation to be used in fixeddose combinations. It should be noted that the potential therapeuticbenefits of combining acamprosate with a neuroleptic drug arc notlimited to combinations that comprise a sustained-release formulation ofacamprosate. They are expected with any acamprosate formulation that istolerated by the patient at a dosage adequate for therapeutic effect.The minimum efficacious dosage will be lower with the sustained-releaseformulations of acamprosate described herein than with Campral®, and thesustained-release formulations described herein may also have a highermaximum tolerable dosage than either IR acamprosate or Campral®.

In another aspect, provided herein are compositions and methods thatcombine acamprosate, in any formulation, such as for example immediatereleast (IR), sustained release (SR), or enteric-coated, etc., withneuroleptic medications, such as those described herein. Examples suchmedications include, without limitation, perphenazine, lamotrigine,quetiapine, others described herein and any other neurolepticmedication.

Some embodiments relate to methods of treating a patient suffering froma disorder requiring treatment with a neuroleptic drug. The methods caninclude selecting a subset of such patients also in need of reducingpsychiatric conditions such as anxiety or depression.

EXAMPLES Example 1

Case 1: A 56-year old woman had long-standing tardive dyskinesia inducedby treatment of schizoaffective disorder with a variety of neurolepticsand mood stabilizers. Her TD was characterized by side to side movementsof the jaw, grimacing movements, rocking of the trunk, and continualinvoluntary kicking, leg-crossing, and twisting movements of her legsand feet. At the time she presented for treatment of her TD she wastreated for her mental illness with lamotrigine and quetiapine, asecond-generation neuroleptic. She was started on Campral® 666 mg threetimes a day, with partial relief of symptoms. When Campral® wasincreased to 999 mg three times a day she had complete relief of her TD.After two months free of symptoms of TD she switched from quetiapine toperphenazine, a first-generation neuroleptic; her TD symptoms did notreturn. After the switch to perphenazine the patient had less daytimesedation than with quetiapine, stopped gaining weight, and had fewersymptoms of anxiety and depression.

After additional weeks free of TD symptoms she discontinued theCampral®. Fler TD symptoms returned, as did feelings of anxiety andagitation that had not been present while she was on the combination ofCampral® and perphenazine.

She resumed Campral®, again finding that 666 mg three times a day didnot give her complete relief, but 999 mg three times a day did. On thisdose she again got relief of anxiety and agitation.

To test the hypothesis that the efficacy of Campral® was related toadequate time above a threshold plasma level the patient was asked totry taking 1332 mg once a day and 666 mg for her other two doses. Onthis dose she continued to be free of involuntary movements of TD, butdid have significant GI side effects of diarrhea and abdominal cramps.

The results showed efficacy of Campral® for TD at a lower total dailydose, when instead of distributing the dose evenly, a larger proportionof the dose was given at one time. This demonstrates that the use ofCampral® at a concentration above a therapeutic threshold value for asufficient number of hours per 24-hour day (e.g., 6-14 hours, preferablyabout 8) can be sufficient to give a 24-hour therapeutic effect. Thecase also shows that individual doses of over 1 gram of Campral® at onetime may be poorly tolerated.

Example 2

CASE 2: A 34-year old man had been treated with Campral® for severalyears for TD due to exposure to several neuroleptics for schizoaffectivedisorder. He was currently treated with lamotrigine and quetiapine forhis mental illness, and was taking Campral® 1332 mg+999 mg+1332 mg on athree times daily basis. This dose of Campral® completely relieved hisinvoluntary movements of TD—the latter including involuntary movementsof the cheeks and mouth, rocking movements of the trunk, and twistingmovements of the both upper and lower extremities. 999 mg three times aday did not give full relief from his involuntary movements. To test thetherapeutic threshold hypothesis the patient was asked to try 1332 mg ofacamprosate once a day in the morning. On this dose he was free ofmovements in the morning and early afternoon but movements returned inthe evening. When he added a second dose of 1332 mg in the lateafternoon—approximately 8 to ours after his first dose—he obtainedcomplete relief of symptoms. He noted that when he got relief of hisinvoluntary movements he also had less anxiety and agitation than whenthe movements were present.

Both of these cases support two hypotheses: 1) That the treatmentresponse to acamprosate calcium in TD (and presumably in otherneuropsychiatric disorders characterized by recurrent unwantedstereotypic symptoms) is related to the amount of time the acamprosateplasma level is above a specific threshold, and not on the AUC of the PKcurve. This is so because in both cases the patient did better onregimens that had a lower total daily dose of acamprosate calcium bututilized either a higher single dose on one occasion or changed thespacing of doses so as to provide a higher plasma concentration ofacamprosate for several hours a day than would be seen with the baselineregimen at steady state. This is unexpected, because it has not beenknown heretofore that lower total daily doses of acamprosate calciumcould work better than higher ones if dosages were divided unevenly orspaced differently during the 24-hour day so as to attain a higherC_(max) at steady state. (2) That the combination of acamprosate calciumwith a neuroleptic can provide relief of anxiety and agitationassociated with psychosis and TD. This is unexpected, becauseacamprosate calcium by itself does not have anti-anxiety effects.

In a dog study of simulated sustained release of acamprosate it wasshown that through sustained release a higher residence time above athreshold can be attained than by giving the same dose all at once.Combining the results from the dog study with the implications of thereported human cases we contemplate that acamprosate delivered by asustained release system can relieve symptoms of TD and otherneuropsychiatric disorders given once or twice a day. A single 800 mgdose of sustained-release acamprosate calcium can produce a residencetime of four hours above a potential single-dose therapeutic thresholdof 200 ng/mL; 666 mg of Campral® did not do this even in the fastingstate and, and would not do so at a dosage of even 1332 mg either, giventhe dose-proportionality of its pharmacokinetics. Thus it appears that atotal daily dose of less than one gram of sustained release acamprosate,given on a twice a day basis, or perhaps even on a once a day basis,could be adequate to treat TD in the case examples. Therefore in somecases—probably the majority of cases—of TD cases the minimum effectivedaily dose of acamprosate delivered by a sustained release system couldbe less than 1 gram—the minimum of the range of efficacious dosagesreported heretofore for the enteric-coated formulation (Campral®). Itshould be noted further that experience to date with the enteric-coatedtablets (Campral®) has never shown them to fully relieve the symptoms ofTD at doses of 1 gram, whereas here in some embodiments daily doses ofless than 1 gram can offer complete symptom relief and not just adetectable therapeutic effect.

Example 3 Sustained Release Formulations of Acamprosate Calcium

The tablets swell when they come in contact with gastric juices; theyare retained in the stomach for several hours if they are administeredin the fed state (e.g., at the conclusion of a meal). If administered inthe fasted state they rapidly (30 minutes-2 hours) move to the smallintestine. The formulation has been manufactured as 400 mg and 800 mgtablets. These are standard round bi-convex white tablets with bevelededges. Both tablet strengths arc spray coated with Opadry® II White(Colorcon, Inc.) for ease of swallowing. Purified water is the vehiclefor the Opadry; it evaporates during the coating process. The totalweight of the coating is between 2% and 4% of the pre-coating weight.

Table 2 shows the ingredients of two tablets (400 mg tablet and 800 mgtablet) having Carbopol 974P® prior to coating:

TABLE 2 Amount Amount (mg) in (mg) in S.R. S.R. 400 mg 800 mg IngredientFunction tablet tablet Acamprosate calcium Active ingredient 400 800Povidone K-90 Binder 50 50 Microcrystalline Diluent 320 100 celluloseColloidal silicon dioxide Glidant 10 10 Citric acid Acidulant 60 0Carbopol 974P Polymer 60 60 Carboxymethylcellulose Polymer 40 40 Starcap1500 Disintegrant 40 40 Talc powder Filler 10 10 Magnesium stearateLubricant 10 10 Total prior to coating 1000 1120

Tablets comprising Carbopol 974P® and 300 mg and 600 mg acamprosatecalcium were also prepared. The Pharmacokinetics of these tablets werefound to be dose proportional.

Example 4 Sustained Release Formulations of Acamprosate Calcium

Table 3A shows ingredients of the granules for preparing tabletscomprising 800 mg of acamprosate and Carbopol® 971P. Tables 3B and 3Cshow the ingredients of two 800 mg tablets having oaring amount ofCarbopol® 971P:

TABLE 3A Granulation: Lot 111113 Material mg gram Acamprosate calcium800 800 PVP K90 50 50 Avicel PH102 100 100 Cabosil 10 10 Total 960 960Water 120 gms

TABLE 3B Blend: Lot 111213-A mg gram Granules, 111113 960 48 Carbopol971 P 60 3 CMC 7HF 40 2 Starcap 1500 40 2 Talc 10 0.5 MGST 10 0.5 Total1120 56

TABLE 3C Blend: Lot 111213-B mg gram Granules, 111113 960 48 Carbopol971 P 80 4 CMC 7HF 20 1 Starcap 1500 40 2 Talc 10 0.5 MGST 10 0.5 Total1120 56

Example 5 Dissolution Profiles of the 400 Mg and 800 Mg SustainedRelease Acamprosate Tablets of Example 3

400 mg or 800 mg tablets were dissolved in either acetate solution (pH4.5) or 1M HCl (pH 1.0). The percentage of the active ingredientreleased into the solution was determined at 1, 2, 4, 6, 8, and 10hours. Each release profile was assessed in six different test vessels.Tables 4-7 display the results, demonstrating that release isapproximately linear with the square root of time. The fourth column ineach table displays the amounts of drug that would be released if therelease were exactly proportional to the square root of time, with aspecified coefficient that ranges from 0.27 to 0.3.

TABLE 4 Release of Acamprosate from 400 mg Tablets from EXAMPLE 3(Sustained release Acamprosate formulation) in Acetate Solution (pH4.5) - (n = 6) Mean % S.D. of % Mini- Maxi- of Total 27% * of Total mummum Time SQRT Drug Re- SQRT Drug Re- % Re- % Re- (hours) Time leasedTime leased leased leased 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 24.0927.00 1.40 23 27 2 1.4142 36.09 38.18 2.34 34 40 4 2.0000 54.39 54.004.02 49 60 6 2.4495 70.11 66.14 4.15 64 76 10 3.1623 87.67 85.38 4.21 8395 12 3.4641 92.31 93.53 4.38 87 99

TABLE 5 Release of Acamprosate from 400 mg Tablets of EXAMPLE 3(Sustained Release Acamprosate formulation) in 0.1N HCl (pH 1.0) - (n =6) Mean % S.D. of % Mini- Maxi- of Total 27% * of Total mum mum TimeSQRT Drug Re- SQRT Drug Re- % Re- % Re- (hours) Time leased Time leasedleased leased 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 31.60 27.00 1.58 2427 2 1.4142 44.83 38.18 3.20 36 41 4 2.0000 63.20 54.00 4.42 56 62 62.4495 75.27 66.14 5.42 69 74 10 3.1623 91.31 85.38 3.59 85 91 12 3.464195.99 93.53 2.96 90 96

TABLE 6 Release of Acamprosate from 800 mg Tablets of EXAMPLE 3(sustained release Acamprosate formulation) in Acetate Solution (pH4.5) - (n = 6) Mean % S.D. of % Mini- Maxi- of Total 30% * of Total mummum SQRT Drug Re- SQRT Drug Re- % Re- % Re- Time Time leased Time leasedleased leased 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 31.60 30.00 1.58 2934 2 1.4142 44.83 42.43 3.20 42 51 4 2.0000 63.20 60.00 4.42 58 64 62.4495 75.27 73.48 5.42 70 84 10 3.1623 91.31 94.87 3.59 87 97 12 3.464195.99 100.00 2.96 91 100

TABLE 7 Release of Acamprosate from 800 mg Tablets of EXAMPLE 3(Sustained release Acamprosate formulation) in 0.1N HCl (pH 1.0) - (n =6) Mean % S.D. of % Mini- Maxi- of Total 29% * of Total mum mum TimeSQRT Drug Re- SQRT Drug Re- % Re- % Re- (hours) Time leased Time leasedleased leased 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 28.11 29.00 1.21 2629 2 1.4142 41.56 41.01 1.77 40 44 4 2.0000 61.48 58.00 2.38 57 63 62.4495 75.41 71.04 1.61 73 77 10 3.1623 92.24 91.71 0.55 92 93 12 3.464196.62 100.00 0.65 96 97

Example 6 Dissolution Profiles of the 400 Mg And 800 Mg SustainedRelease Acamprosate Tablets of Example 3

Tables 8-10 display the results of contacting the tablets described inExample 4 with either acetate solution (pH 4.5) or 1M HCl (pH 1.0). Theresults in Tables 9 and 10 are also illustrated in FIGS. 1-4, showingthat the dissolution profile is substantially proportional to the squareroot of time.

TABLE 8 Swell test of 800 mg Tablets of EXAMPLE 4 Lot No: 111213-A111213-B Medium: HCl Acetate HCl Acetate Initial Length (cm) 1.28 1.281.28 1.28 Length 5 min (cm) 1.4 1.4 1.45 1.45 Length 30 min (cm) 1.5 1.51.55 1.5 Length 1 hr (cm) 1.55 1.52 1.6 1.52 Length 2 hr (cm) 1.65 1.551.7 1.55 Length 6 hr (cm) 1.9 1.65 1.95 1.7 % Swelling 148% 129% 152%133% Firmness Rating 4.5 4 4.8 4 Initial Thick (cm) 0.77 0.78 0.78 0.78Final Thick (cm) 1.5 1.3 1.55 1.3 % Swelling 195% 167% 199% 167%

Observations:

-   1) The Swelling results are comparable to SNC-102 tablets.-   2) No erosion is seen.-   3) % Swelling is more in lot 111213-B compared to lot 111213-A-   4) The swollen tablets are intact and firm for 6 hours during the    swelling test.

Firmness Rating System:

-   1. Shapeless after 6 hours in acid-   2. Loosely retains shape, very soft-   3. Retains shape, but offers no resistance-   4. Can be picked up, slight resistance-   5. Very firm and elastic

TABLE 9 Dissolution Profile of 800 mg Tablets of EXAMPLE 4 in HClSolution HCL Time (hours) SQ of Time 111213-A 111213-B 0 0 0 0 1 1 30.2129.97 2 1.4142 42.22 44.21 4 2 58.63 62.71 6 2.4495 70.15 74.75 103.1623 84.94 89.04 12 3.4641 88.14 92.79

TABLE 10 Dissolution Profile of 800 mg Tablets of EXAMPLE 4 in AcetateSolution Time (hours) 111213-A 111213-B 0 0 0 1 36.41 34.24 2 49.7547.42 4 68.76 64.53 6 80.72 77.94 10 93.94 92.93 12 96.34 95.68

Example 7 Combination of Reformulated Acamprosate with First-generationNeuroleptics

First-generation neuroleptic (antipsychotic drugs) have been used forover 50 years in the treatment of schizophrenia and other psychoticdisorders, as well as in the treatment and prevention of nausea andvomiting. The first of these drugs to be introduced to the market waschlorpromazine; others include thioridazine, perphenazine,trifluoperazinc, haloperidol, fluphenazine, loxapinc, and molindone.Their common feature is that they are all dopamine antagonists at bothD2 and D3 dopamine receptors; each has its own distinctive set ofeffects on receptors for other neurotransmitters. One of the majordrawbacks of these drugs is their propensity to cause movementdisorders. With acute administration they can cause movement disordersincluding Parkinsonism (tremor, rigidity, bradykinesia and gaitinstability) as well as dystonia, dyskinesia, and akathisia. Givenchronically they can cause chronic movement disorders that persist evenif the drug is stopped and may even be permanent. These disordersinclude tardive dyskinesia (TD), tardive dystonia, and tardiveakathisia. The incidence of TD and other tardive movement disorders withlong-term use of first-generation neuroleptics exceeds 25%, with an evenhigher rate in elderly patients. In part because of the very high riskof TD, a second generation of neuroleptics was developed that has alower risk of causing TD and related movement disorders with chronicadministration. These drugs include risperidone, quetiapine, clozapine,olanzapine, and aripiprazole. The incidence of TD with these drugs isless than 5%, but all are associated with metabolic side effects ofsufficient severity to affect life expectancy. These side effectsinclude weight gain, glucose intolerance, and disturbances in lipidmetabolism. With the exception of clozapine the second-generationneuroleptics are not more effective in treating schizophrenia and otherpsychotic disorders. Clozapine, while more effective as treatment forsevere mental illness, has additional serious medical side effectsincluding a significant incidence of agranulocytosis that requiresfrequent monitoring of patients' white blood cell counts as arequirement for using the drug. The first generation neuroleptics,especially the higher-potency ones, have a much lower incidence ofmetabolic side effects than the second-generation neuroleptics, and somefirst generation neuroleptics, e.g., molindone, do not have them at all.

If first generation neuroleptics could be given without a high risk ofcausing or exacerbating tardive dyskinesia they would be preferable tosecond-generation neuroleptics for treating most patients with psychoticdisorders as they would lack the troublesome metabolic side effects ofthe latter. (While many patients would have some degree of acuteextrapyramidal side effects from the first-generation antipsychoticdrugs, these often can be managed by either reducing the dose, switchingto a less potent agent, or adding an antiparkinsonian drug. Tolerancecan develop to acute extrapyramidal side effects as well. TD and relatedpotentially-irreversible tardive movement disorders remain the singlegreatest drawback to the use of the first generation antipsychoticdrugs.) Some embodiments herein relate to utilizing fixed-dosecombinations of first-generation neuroleptics with new formulations ofacamprosate designed for delayed release via a sustained releasedelivery system. Such combinations would not have been practicalheretofore because of the high doses of acamprosate needed to treat TDif the existing enteric-coated tablet formulation is used. Given thecompliance issues common among psychiatric patients a regimen of morethan two pills daily would risk diminished effectiveness. Ifsignificantly more than a gram of acamprosate were needed to treat TDthe combination of an effective dose of acamprosate for TD with aneffective dose of a first-generation neuroleptic would need to bedivided among at least three pills, as a dose of enteric-coatedacamprosate significantly larger than 500 mg in a single pill mightrequire that pill to be unpleasantly large, even without the addition ofa second drug. The actual dosage of enteric-coated acamprosate needed totreat TD might in fact be much higher—more than 3 grams in some cases.On the other hand, if the needed dose of different formulation ofacamprosate needed were less than one gram, treatment effective for bothpsychosis and TD could be delivered by one or two combination pills.Such is the case with the instant formulations described herein thatprovide for sub-gram dosages and formulations of acamprosate.

While it is not known whether co-administration of acamprosate with aneuroleptic drug will completely prevent the emergence of TD in allcases, it can be expected that it will diminish the severity of any TDthat does develop, and that it acamprosate might suppress symptoms of TDif it continues to be given, even if some dyskinesia could appear if theacamprosate were discontinued. In the two case examples, patients withestablished TD and a mental disorder took acamprosate together with aneuroleptic and had complete relief of their TD symptoms. Those patientswould also be free of TD symptoms if they took the same combinationwithout having TD at baseline. The incidence of TD will be lower if afirst generation neuroleptic is co-administered with a dose ofacamprosate that would be efficacious to treat established TD in themajority of patients. If TD did develop in some patients the severitywould necessarily be less than if acamprosate were not given.

Some embodiments therefore relate to among other things the followingtwo technologies: (1) Compositions containing a dose of a firstgeneration neuroleptic adequate to treat a psychotic disorder and a doseof acamprosate adequate to treat or prevent tardive dyskinesia,including compositions in which the doses of the neuroleptic and theacamprosate are combined in a single pill, and compositions in which thedoses arc divided into multiple units delivered concurrently, e.g., onetablet of each drug in a single blister pack ; and (2) The use of suchcompositions to treat one or more of schizophrenia, bipolar disorder,schizoaffective disorder, depression with psychotic features, delusionaldisorder, other psychotic conditions, the symptoms of hallucinations anddelusions. The compositions in some aspects further can treat or preventthe symptoms of nausea and vomiting that often accompany the use of suchmedications. Tn the described technologies the use may be in patientswith or without established TD. The preferred formulation of acamprosatewould be a sustained release formulation of the type described herein,though compositions utilizing other formulations of acamprosate could beeffective for the purpose if the dose of acamprosate were adequate.

It is surprising and unexpected that in some embodiments doses ofacamprosate lower than the heretofore-described dosing range fortreating TD can be effectively used, even though such lower doses maynot have the same PK profiles as the enteric-coated pills utilized inpreviously-described treatment of TD—and such lower doses can in someembodiments produce a 24-hour AUC lower than that produced by similarlyefficacious doses of enteric-coated acamprosate. Further, we note theunexpected finding that patients with TD and mental disorders whoreceived acamprosate together with a neuroleptic showed an unexpectedimprovement in anxiety and agitation, even though acamprosate alone doesnot affect these symptoms.

It should be evident that to attain therapeutic advantages describedherein from the pharmacokinetics described, which are different incritical ways both from IR acamprosate and from the marketed formulationof acamprosate, the specific technology for formulating the sustainedrelease delivery system for acamprosate does not matter as long as thatsystem that can delivers substantially equivalent PK curves in the fedand the fasting state. This will follow from the formulation havingsubstantially equivalent in vitro release kinetics, and being aformulation that will release its active ingredient in the same wayregardless of its location in the GI tract.

TABLE 11 lists first-generation neuroleptic drugs and range of dailydosages at which they are usually prescribed. Some embodiments hereinrelate to tablets or capsules that implement one of the sustainedrelease technologies in Table 12 delivering a dosage of acamprosatebetween 200 and 1000 mg, together with a dose of one of the drugsdescribed in TABLE 11 at one of the dosages specified in that table or adosage of one-half of the minimum dose in the table below, and up to themaximum dose or any value there between. As an example, a tablet mightcomprise 4 mg of perphenazine together with 250 mg of acamprosateformulated in a sustained release preparation, with the perphenazinesurrounding a core of acamprosate, or alternatively mixed with theacamprosate throughout the tablet.

TABLE 11 First Generation Neuroleptics and Metoclopramide: Daily Dosagesand Doses for Fixed-Dose Combination Pills. Example Single Pill DailyDose Range Dosages (mg) in Combination Drug (mg) with AcamprosateThioridazine 10-200 10, 25, 50, 100 Chlorpromazine 25-200 25, 50, 100Thiothixene 2-50 2, 5, 10, 25 Trifluoperazine 5-50 5, 10, 25Fluphenazine 2-50 2, 5, 10, 25 Haloperidol 0.5-50   0.5, 1, 2, 5, 10, 20Perphenazine 2-32 2, 4, 8, 16 Loxapine 10-100 1, 10, 25, 50 Molindone10-200 10, 25, 50, 100 Metoclopramide 5-60 5, 10, 15

Example 8 Combination of Acamprosate with Second-generation Neuroleptics

The dose of sustained release acamprosate can be between 200 mg and 1000mg. Regarding the neuroleptic dosage, the principle is that the minimumdose is approximately one-half of the smallest currently marketed doseof the drug. Examples of the dosage ranges of some non-limiting examplesof first-generation neuroleptics are given in TABLE 11. Examples ofdosage ranges for some second-generation neuroleptics are shown in thefollowing TABLE 12. For example, the dosage for the neuroleptic canrange from one-half of the minimum dose in the table below, and up tothe maximum dose, or any value there between:

TABLE 12 Neuroleptic Minimum Dose Maximum Dose aripiprazole 1 mg 30 mgasenapine 1 mg 10 mg iloperidone 1 mg 24 mg lurasidone 10 mg  120 mg olanzapine 1 mg 20 mg paliperidone 1 mg 12 mg quetiapine 12.5 mg   400mg  risperidone 0.25 mg    4 mg ziprasidone 10 mg  80 mg

Example 9 Combination of Acamprosate with SSRI and SSRI Antidepressants

SSRIs and SNRIs are efficacious in OCD and PTSD, both conditions thatalso can respond to treatment with acamprosate. Also, SSRIs and SNRIsare used to treat depressive and anxiety disorders in which recurrent,unwanted, stereotyped thoughts, perceptions, and behavior may be part ofthe syndrome. Since acamprosate and the serotonin reuptake inhibitorshave different mechanisms of action, their therapeutic effects on thesedisorders can be synergistic. A published study describes augmentationof the benefits of an SSRI for generalized anxiety by adding Campral® ata dose of 333 mg TID. (Reference)). The fact that sustained releaseacamprosate can be efficacious at a daily dose of less than one gram aday, on a once or twice daily schedule, makes fixed-dose combinations ofsustained release acamprosate with an SSRI or SNRI feasible.

The dose of sustained-release acamprosate can be between 200 mg and 800mg. Some embodiments relate to combinations where the minimum dose isapproximately one-half of the smallest currently-marketed dose of thedrug, for example one-half of the minimum dose in the table below, andup to the maximum dose or any value there between.

TABLE 13 SSRI or SNRI Minimum Dose Maximum Dose Citalopram   5 mg  40 mgDesvenlafaxine   25 mg 100 mg Duloxetine   5 mg  60 mg Escitalopram  2.5mg  20 mg Fluoxetine   5 mg  40 mg Fluvoxamine 12.5 mg 100 mgMilnacipran 6.25 100 mg Paroxetine   5 mg  40 mg Sertraline 12.5 mg 200mg Venlafaxine 12.5 mg 150 mg

Example 10

The pharmacokinetic properties of the specific sustained releasepreparation of acamprosate described in EXAMPLE 3 were tested in humansubjects (healthy male volunteers of age over 18 years) in single-centerPhase I studies. Specific issues addressed in the studies were: (1) Doseproportionality of pharmacokinetics of the EXAMPLE 3 formulation; (2)Comparison of acamprosate described in EXAMPLE 3 with IR acamprosate(acamprosate solution); (3) Comparison of the EXAMPLE 3 formulation withthe marketed formulation of enteric-coated acamprosate tablets(Campral®) in the fed state and the fasting state; and (4) Comparison ofthe pharmacokinetics of the EXAMPLE 3 formulation in the fed and thefasting state. The main findings of the studies show that the EXAMPLE 3formulation has pharmacokinetic properties that make it therapeuticallysuperior both to Campral® and to IR acamprosate, and, that the EXAMPLE 3formulation has the remarkable, unexpected and therapeutically relevantproperty that its pharmacokinetics are equivalent in the fed and thefasting state.

Example 11

In the first study, subjects received, 30 minutes after a standardhigh-fat meal, a single dose of 400 mg of sustained release acamprosate(EXAMPLE 3), of 800 mg of sustained release acamprosate (EXAMPLE 3), orof 666 mg of enteric-coated acamprosate (Campral®). Plasmaconcentrations of acamprosate were determined at within 1 hour(pre-dose) of dosing and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48hours after dosing and pharmacokinetic parameters were calculated.

11 subjects were dosed with 400 mg sustained release acamprosateformulation, 11 subjects were dosed with 800 mg sustained releaseacamprosate formulation, in tablets, and 12 were subjects dosed withCampral® 666 mg. Results are presented in TABLES 14-15 below.

Dose Proportionality: SR acamprosate was readily absorbed following asingle oral dose of sustained release acamprosate formulations, both 400and 800 mg doses. Median T_(max) occurred at 4.00 hours post dose forboth the 400 mg and 800 mg doses; the range of T_(max) was 3.00-5.00hours for the 400 mg dose and 3.00-6.00 hours for the 800 mg dose. MeanC_(max) was 299 ng/mL for the 800 mg dose, which was essentially twicethe mean value of 148 ng/mL for the 400 mg dose. Mean AUC_(o-t) andAUC_(0-∞) for the 800 mg dose of sustained release acamprosate were 4440and 4600 h·ng/mL, respectively. Mean AUC_(o-t) and AUC_(o-∞), for the400 mg dose of sustained release acamprosate were 2220 and 2240 h·ng/mL,respectively. The AUC_(0-t) for the 800 mg dose was exactly twice thatfor the 400 mg dose, and the AUC_(0-∞)for the 800 mg dose was minimallygreater than that for the 400 mg dose. The data for C_(max), AUC_(o-t),and AUC₀₋₂₈ indicate dose proportionality of PK parameters for singledoses of sustained release acamprosate formulations.

The mean apparent terminal half-life of the 800 mg dose of sustainedrelease acamprosate formulation and the 400 mg dose of sustained releaseacamprosate formulation was 12.6 and 12.7, respectively, indicating thatthe half-life of acamprosate was essentially independent of dosestrengths of sustained release acamprosate formulation. This observationpermits inferences about the likely steady-state residence times abovethe therapeutic threshold when the sustained-release formulation isdosed long-term on a QD ore BID basis.

TABLE 14 Dose Proportionality of Pharmacokinetics of SR AcamprosateAdministered in the Fed State to Healthy Male Volunteers 800 mg 400 mgTreatment sustained release sustained release Parameters N Mean ± SD NMean ± SD C_(max), ng/mL 11  299 ± 67.2 11   148 ± 60.4 T_(max), h^(a)11 4.00 (3.00-5.00) 11 4.00 (3.00-6.00) AUC₀₋₄₈, h · ng/mL 11 4440 ±1090 11 2220 ± 724 AUC_(0-∞), 8 4600 ± 1170 5 2240 ± 665 h · ng/mL^(b)t_(1/2), h 8 12.6 ± 4.42 5  12.7 ± 5.75 ^(a)median (range) is reportedfor this parameter. ^(b)AUC to infinity and the T1/2 could not becalculated in all 11 subjects because the terminal part of the PK curvecould not be fitted using standard software in all of the subjects.

The comparison of dose-normalized PK parameters among Campral® and thetwo sustained-release formulations, all three administered in the fedstate (30 minutes after a high-fat meal) are presented below presentedbelow and in FIG. 5. The data indicated rate and extent of absorption ofacamprosate of 800 mg sustained release formulation and 400 mg sustainedrelease formulation, as reflected by systemic exposure C_(max) andAUC₀₋₄₈ values, were dramatically faster and higher than those withCampral® 666 mg under fed conditions. For example, in the fed state 800mg of Campral would not even attain a Cmax of 100 ng/mL, let aloneattain a residence time of several hours above 200 ng,/mL. Thediscussion of food effect in the Campral® package insert would notprepare one for a more than three-fold difference in Cmax betweenCampral and the SR version in the fed state. The data in Table 15 implythat even four Campral tablets—1132 mg, would not reliably provide apeak plasma level over 200 ng/mL if the drug were taken in the fedstate.

TABLE 15 Comparison of Dose-Normalized Pharmacokinetic ParametersBetween Campral ® and Sustained-Release Acamprosate Calcium Administeredto Healthy Male Volunteers in the Fed State GM (95% CI)a DNC_(max)*DNAUC0-48* DNAUC0-∞* T_(max)** Formulation N (ng/mL) (hr · ng/mL) (hr ·ng/mL) (hr) 800 mg sustained 11 244 3607 NR 4.00 release (207, 288)(3191, 4076) (3.00-5.00) 400 mg sustained 11 229 3570 NR 4.00 release(177, 297) (2783, 4581) (3.00-6.00) Campral ® 666 mg 8 73 1684 NR 12.00(56, 96) (1199, 2366) (10.00-24.00) GMR [90% CI] Comparison C_(max)***AUC0-48*** AUC0-∞*** 800 mg sustained release vs. 333.11 214.14 NRCampral ® 666 mg [269.40, 411.90] [169.27, 270.90] 400 mg sustainedrelease vs. 312.74 212.00 NR Campral ® 666 mg [240.48, 406.72] [167.04,269.06] 400 mg sustained release vs. 93.88 99.00 NR 800 mg sustainedrelease [77.67, 113.48] [84.66, 115.76] aGM = Geometric least-squaresmean; CI = Confidence interval; *Back-transformed least squares mean andconfidence interval from mixed effects model performed on naturallog-transformed values. C_(max), AUC₀₋₄₈ and AUC_(0-∞) of acamprosatewere normalized to 666 mg. DNC_(max) is the dose normalized C_(max);DNAUC₀₋₄₈ is the dose normalized AUC₀₋₄₈;. DNAUC_(0-∞) is the dosenormalized AUC_(0-∞). All parameters were normalized to a dose of 800mg. **Median (Minimum, Maximum). ***GMR = Geometric least-squares meanratio between Treatments. NR: Not reportable since most subjects'AUC_(0-∞) at Treatment C (Campral ® 666 mg) were not estimable.Treatment A: 800 mg sustained release acamprosate formulation(Synchroneuron Inc.); Treatment B: 400 mg sustained release formulation(Synchroneuron Inc.); Treatment C: Campral ® 666 mg (as two 333 mgtablets) (Forest Pharmaceuticals, Inc.)

Under fed conditions, the relative bioavailability of the 00 mgsustained-release formulation and of the 400 mg sustained releaseformulation compared to Campral 666® mg were 214% and 212%,respectively. The relative Cmax were 333% and 313%, respectively.

Single doses of 800 mg and 400 mg EXAMPLE 3 sustained releaseformulations were safe and well tolerated when administered 14 daysapart in healthy adult males. No gastrointestinal adverse events werereported, in keeping with clinical experience that GT side effects ofacamprosate are less when the medication is taken with food.

Example 12

In another study subjects received 800 mg of sustained releaseacamprosate formulation of EXAMPLE 3 in the fasted state, 800 mg ofsustained release acamprosate formulation of EXAMPLE 3 in the fed state.For comparison, another study was conducted where subjects received 666mg of enteric-coated acamprosate (Campral®) in the fasted state or 666mg of enteric-coated acamprosate (Campral®) in the fed state. Resultsare depicted in FIGS. 6 and 7 and the following Tables 16 and 17.

TABLE 16 Fed State and Fasting State Plasma Concentrations FollowingOral Administration of 800 Mg of Sustained-Release Acamprosate CalciumTablets to 12 Healthy Male Volunteers Mean Plasma Concentration ng/mL SRAcamprosate Ca 800 mg/ SR Acamprosate Ca 800 mg/ Time (hr) Fed Fasted 00 0 1 96 196 2 233 263 3 292 266 4 291 271 5 230 231 6 199 185 8 149 11210 127 87 12 88 75 18 63 65 24 52 61 36 39 40 48 47 42

TABLE 17 Fed State and Fasting State Plasma Concentrations FollowingOral Administration of 666 Mg of Enteric-Coated Acamprosate CalciumTablets (Campral ®) to Six Healthy Male Volunteers Mean PlasmaConcentration (ng/mL) Time (hr) Campral ® 666 mg/Fed Campral ® 666mg/fasted 0 0 0 1 0 0 2 0 11 3 0 52 4 0 106 5 0.4 135 6 2 140 8 10 13510 30 101 12 83 90 18 53 84 24 63 80 36 40 49 48 37 36

It is immediately evident that the pharmacokinetics of SR acamprosatecalcium are very similar in the fed and fasting state; in fact they arcbioequivalent according to FDA criteria. On the other hand thepharmacokinetics of Campral® are dramatically different in the fed andfasting state. In the data presented both C_(max) and AUC₍₀₋₄₈₎ in thefed state are 41% lower than in the fasting state.

These pharmacokinetic data show that the SR acamprosate formulations ofExample 3 are able to produce a mean acamprosate blood level greaterthan 200 ng/ml for more than four hours after a single 800 mg dose,whether it is given in either the fed or the fasting state. By contrast,assuming dose proportionality for Campral®, an 800 mg dose of Campral®would not attain this threshold in either the fed state or the fastingstate. In fact, an 800 mg dose of Campral® in the fed state wouldproduce a Cmax of only 100 ng/ml. A clear implication is that at equalmilligram dosages SR acamprosate of EXAMPLE 3 will be more efficaciousin treating neuropsychiatric disorders than Campral.

The formulations of the sustained release technology, including those ofEXAMPLE 3, are grossly superior to Campral® in the fed state becausethey are much more bioavailable. In the fasting state the formulationshave a C_(max) 45% higherthan the C_(max) expected for an 800 mg dose ofCampral®, based on the C_(max) observed with the 666 mg dose andpresuming dose proportionality. The higher C_(max) implies a longerresidence time at the threshold level necessary for therapeuticefficacy.

Given the large negative effect of administration with food on thebioavailability of Campral® tablets it is very surprising that there isno food effect at all on the bioavailability of the new formulationsdescribed herein. The observed bioequivalence of new formulations hereinin the fed and fasting states implies that the adverse effect of food onthe absorption of acamprosate in the intestines is exactlycounterbalanced by the benefits for absorption of the sustained releaseof acamprosate into the stomach in the fed state. This equality ofopposing effects is quite unusual and could not have been predicted fromwhat is known about acamprosate and its previously known formulations.

Example 13

Four human volunteer groups were compared in this Phase 1 study: (A) 800mg sustained release acamprosate tablets (in the fed state), (B) 800 mgsustained release acamprosate tablets (in the fasting state), (C)Campral® 666 mg (in the fasting state), and (D) acamprosate calcium 800mg oral solution in water (in the fasting state). Plasma samples werecollected within 1 hour (pre-dose) of dosing and 1, 2, 3, 4, 5, 6, 8,10, 12, 18, 24, 36 and 48 hours after dosing.

TABLE 18 Summary (Mean and SD) of Pharmacokinetic Parameters forAcamprosate Plasma Pharmacokinetic Parameters in Healthy SubjectsAdministered Treatment A, B, C, and D Campral ® 666 mg 800 mg sustained800 mg sustained Tablets, Fasting Acamprosate Calcium release Tablets,release Tablets, (dose normalized 800 mg solution, Fed Fasting results)Fasting Parameters N Mean ± SD N Mean ± SD N Mean ± SD N Mean ± SDC_(max), ng/mL 12  309 ± 108 12 322 ± 156 6 179 ± 106 6  528 ± 206T_(max), h^(a) 12 3.00 [2.00, 4.00] 12 2.00 [1.00, 4.00] 6 8.00 [4.00,12.00] 6 1.00 [1.00, 2.00] AUC₀₋₄₈, 12 3970 ± 841 12 3870 ± 1040 6 3400± 1050 6 5030 ± 576 h · ng/mL : median [range]; NA; Not applicable;Treatment A: 800 mg sustained release tablets (Synchroneuron Inc.) underfed conditions; Treatment B: 800 mg sustained release tablets(Synchroneuron Inc.) under fasting conditions; Treatment C: Campral ®666 mg (two 333 mg tablets) (Forest Pharmaceuticals, Inc.) under fastingconditions; Treatment D: Acamprosate calcium 800 mg oral solution inwater (Synchroneuron Inc.) under fasting conditions.The results:

-   (1) Confirm that SR acamprosate has equivalent AUC and C_(max) in    the fed and the fasting state;-   (2) Show that the mean dose-normalized AUC of Campral® in the    fasting state was 88% of the AUC of SR acamprosate in the fasting    state, but the mean C_(max) for Campral® was only 56% of the mean    C_(max) for SR acamprosate. Thus, the residence time of Campral®    above a therapeutic threshold will be lower than that attained by SR    acamprosate, and in some cases SR acamprosate will attain a    therapeutic threshold blood level while Campral® at the same dose    will not, even when the drug is taken in the fasting state.-   (3) Show that acamprosate solution is more bioavailable than SR    acamprosate in the fasting state, with AUC for the solution being    30% higher than the AUC for SR acamprosate. However, the C_(max) for    the solution was 64% higher. The disproportionately higher C_(max)    for the solution implies that the dose of solution needed to attain    a given time above a therapeutic threshold will give a higher    C_(max) than the dose of SR acamprosate needed to attain the same    therapeutic residence time. A higher Cmax implies a greater    potential for adverse effects related to the plasma level of    acamprosate. And, acamprosate solution (or IR acamprosate tablets,    because acamprosate is highly soluble in gastric or intestinal    juices) will have a greater potential for side effects caused by a    high local concentration of acamprosate or its associated cation in    the GI tract. These facts together imply greater tolerability of SR    acamprosate than IR acamprosate. (It is likely that Campral®was    developed as an enteric-coated tablet because of concerns about GI    side effects if an acamprosate tablet dissolved immediately in the    stomach.). Furthermore, the bioavailability of IR acamprosate    solution is reduced when it is taken in the fed state (REF), a    problem not encountered with SR acamprosate. Thus, SR acamprosate is    therapeutically superior to acamprosate solution in three ways: (1)    Tt is more convenient to take a tablet than a liquid; (2) Gl    tolerability and possibly systemic toxicityare likely to be worse    with the solution both because of a higher local concentration of    the drug in the stomach and a higher plasma C_(max) for a given    residence time above a therapeutic threshold; and (3) SR acamprosate    can be taken with food if desired without a loss of therapeutic    effect, implying better treatment adherence and better GI    tolerability, the latter because patients often tolerate medications    if taken with food that cause GI upset if taken on an empty stomach.    IR acamprosate tablets would be more convenient than acamprosate    solution but would still be inferior to SR acamprosate.

Food Effects on Pharmacokinetics of 800 mg Sustained Release Tablets

The mean C_(max) was 309 or 322 ng/mL, respectively, when 800 mgsustained release acamprosate formulation was dosed under fed andfasting conditions. The median Tmax in the fed group was one hourgreater (3 hours vs. 2 hours) than that in the fasting group.

The rate and extent of absorption of 800 mg sustained-releaseacamprosate tablets, as reflected by peak exposure of C_(max) andsystemic exposure of AUC_(o-t) values, were comparable (96.75% and103.13%, respectively) between the test and reference treatments. Theresults indicate that there was no food effect on 800 mg sustainedrelease acamprosate tablet in the rate and extent of absorption.

The 90% confidence interval for the geometric mean ratios of C_(max) ofacamprosate between the subjects taking SR acamprosate under the fedcondition and the same subjects taking SR acamprosate in the fastingcondition was [74.39%, 125.84%]. The 90% confidence interval for thegeometric mean ratios of AUC_(o-t) of acamprosate between the testtreatment group (fed conditions) and the reference treatment group(fasting condition) was [88.74%, 119.85%].

TABLE 19 Statistical Comparisons of Acamprosate Plasma PharmacokineticParameters in Healthy Male Volunteers Administered Single Oral Doses of800 Mg Sustained Release Tablets under Fed and Fasting Conditions Ratioof Ratio of AUC AUC AUC AUC (0-8) to AUC (0-12) to Drug N (0-8 h) (0-12h) (0-48) AUC (0-48) AUC (0-48) SR Acamprosate - Fasted 12 1621 19833872 0.416 0.512 SR Acamprosate - Fed 12 1593 2086 3967 0.400 0.525Campral - Fasting 6 144.8 377.0 2168 0.0632 0.164 Campral - Fed 12 6681098 3418 0.191 0.317 Note: AUC(0-t) was calculated from the point PKdata by linear interpolation. Means are arithmetic means. Mean ratio isthe mean of the individual subjects' AUC ratios (not the ratio of theindividual subjects mean AUCs.) AUC Unit: ng*hr/mLFasting State Statistical Comparison of 800 mg SR Acamprosate Tabletsvs. Acamprosate Calcium 800 mg Oral Solution

When healthy male volunteers received in the fasting state single oraldoses of 800 mg acamprosate SR tablets and 800 mg acamprosate calciumsolution the mean C_(max) were322 and 528 ng/mL, respectively. Themedian T_(max) in the tablet group was one hour longer (2 hours vs. 1hour) than that in the solution group.

The rate and extent of absorption of the test formulation (800 mgsustained release tablets) of acamprosate, as reflected by peakexposures C_(max) and systemic exposures AUC₀₋₄₈ values, were slower(40.53%) and lower (24.81%) than those with the reference formulation(acamprosate calcium oral solution), respectively, under fastingconditions.

The 90% confidence intervals for the geometric mean ratios of theC_(max) and the dose normalized AU₀₋₄₈ of acamprosate between 800 mgsustained release acamprosate tablets acamprosate calcium oral solution)were ([41.57%, 85.09%]) and ([61.48%, 91.96%]), respectively.

The results indicate that under fasting conditions the relativebioavailability of the 800 mg SR acamprosate tablet compared toacamprosate calcium oral solution was 75.19%.

TABLE 20 Statistical Comparisons of Acamprosate Plasma PharmacokineticParameters in Healthy Male Volunteers Administered Single Oral Doses of800 Mg Sustained Release Tablets and Acamprosate Calcium 800 Mg OralSolution under Fasting Conditions GM (95% CI)^(a) C_(max)* AUC₀₋₄₈*AUC_(0-∞)* T_(max)** Treatment N (ng/mL) (hr · ng/mL) (hr · ng/mL) (hr)800 mg SR Tablets 12 247 [190, 3134 [2670, NA 2.00 [1.00, 4.00] 322]3679] Acamprosate Calcium Oral  6 416 [290, 4168 [3427, NA 1.00 [1.00,2.00] Solution 597] 5068] GMR (in %)[90% CI] Comparison C_(max)***AUC₀₋₄₈*** SR Tablets vs. Acamprosate Calcium Oral 59.47 [41.57, 75.19[61.48, 91.96] Solution 85.09] ^(a)GM—Geometric least-squares mean;CI—Confidence interval; *Back-transformed least squares mean andconfidence interval from mixed effects model performed on naturallog-transformed values. C_(max), AUC₀₋₄₈ and AUC_(0-∞) of acamprosatewere normalized to 666 mg. **Median (Minimum, Maximum). ***GMR =Geometric least-squares mean ratio between Treatments. NA: Not availablesince AUC_(0-∞) could not be estimated for most subjects.Fasting State Statistical Comparison of 800 mg Sustained ReleaseAcamprosate Formulation vs. Campral® 666 mg

When 800 mg sustained release acamprosate tablets and Campral® 666 mgwere dosed under fasting conditions the mean dose-normalized C_(max)were 322 and 179 ng/mL, respectively, when 800 mg sustained releaseacamprosate formulation and. The median T _(max) in 800 mg sustainedrelease formulation group was 6 hours shorter (2 vs. 8 hours) comparedto that in Campral® 666 mg group.

The rate of absorption of the test formulation (800 mg sustained releasetablet) of acamprosate, as reflected by peak exposures C_(max) values,was faster (55.14%) compared to that of the reference formulation(Campral® 666 mg) under fasting conditions.

The extent of absorption of the test formulation (800 mg sustainedrelease tablet) of acamprosate, as reflected by systemic exposuresAUC_(o-t) value, was comparable, 96.06%, to Campral® 666 mg underfasting conditions.

The 90% confidence intervals for the geometric mean ratios of thedose-normalized C_(max) and the dose-normalized AUC_(o-t) of acamprosatebetween the 800 mg sustained release formulation and Campral® 666 mgwere [108.43%, 221.96%] and [78.55%, 117.48%], respectively, based onthe statistical comparison results.

Thus, the results indicate that acamprosate is absorbed faster from thesustained release formulation, with the extent of absorption similar toCampral® 666 mg.

TABLE 21 Statistical Comparisons of Acamprosate Plasma PharmacokineticParameters in Healthy Subjects Administered Single Oral Doses 800 MgSustained Release Tables and Campral ® 666 Mg Tablets Under FastingConditions GM (95% CI)^(a) DNC_(max)* DNAUC₀₋₄₈* DNAUC_(0-∞)* T_(max)**Treatment N (ng/mL) (hr · ng/mL) (hr · ng/mL) (hr) 800 mg sustainedrelease 12 247 [190, 3134 [2670, 3679] NA 2.00 [1.00, Tablets 322] 4.00]Campral ® 666 mg (2 ×  6 159 [111, 3262 [2682, 3967] NA 8.00 [4.00, 333mg) Tablets 229] 12.00] GMR (in %) [90% CI] Comparison C_(max)***AUC₀₋₄₈*** 800 mg sustained release tablets vs. Campral ® 155.14[108.43, 96.06 [78.55, 117.48] Tablets 221.96] ^(a)GM = Geometricleast-squares mean; CI = Confidence interval; *Back-transformed leastsquares mean and confidence interval from mixed effects model performedon natural log-transformed values. C_(max), AUC₀₋₄₈ and AUC_(0-∞) ofacamprosate were normalized to 666 mg. **Median (Minimum, Maximum).***GMR = Geometric least-squares mean ratio between Treatments. NA: Notavailable since AUC_(0-∞) could not be estimated for most subjects.Treatment B: 800 mg sustained release tablets (Synchroneuron Inc.) underfasting conditions Treatment D: Campral ® 666 mg (as two 333 mg tablets)(Forest Pharmaceuticals, Inc.) under fasting conditions

Example 16

The highly unexpected finding of equivalent pharmacokinetics of the SRformulation in the fed and fasting states raised the question of whetherthe SR formulation tablet had the same fate in the fed and fastingstates—whether, contrary to expectations, the tablet was retained in thestomach in the fasting state for several hours. Typically even largetablets are quickly ejected from the stomach by powerful “housekeepingwaves” produced by intense periodic contractions of gastric muscles.

To answer the question a gamma scintigraphic study was undertaken usingradiolabeled SR tablets according to EXAMPLE 3, which were taken byvolunteer subjects in both the fed state and the fasting state. As willbe seen, the study showed that the fate of the tablet differs greatlybetween the fed and fasting states; it is retained in the stomach formany hours in the fed state—4.5 hours in one of six subjects and over 16hours in the remaining 5 - and rapidly ejected into the small intestinein the fasted state. The study supports the following hypothesis for themechanism underlying the fed-fasting pharmacokinetic equivalence of thesustained-release tablets: In the fed state, almost all of theacamprosate released by the SR tablet would be released in the stomach,and therefore the drug would be (would be exposed for potentialabsorption to the entire surface of the small intestine. By contrast,much of the acamprosate released by the tablet taken in the fastingstate is released more distally in the small intestine—typically in theileum. Relative to the SR tablet in the fasting state, the SR tablet inthe fed state presents more of the acamprosate to the entire smallintestine. Since the bulk of the absorption of acamprosate is bydiffusion this increase in the area of intestinal surface to which thedrug is exposed over time increases absorption in the fed state. In thefasting state relative to the fed state, the pill reaches the jejunum inless than 0.5 to 2.5 hours, before it has released even half of thedrug. Differences between fed state and fasting state pharmacokineticsrelate to the movement of the SR tablet through the GI tract, to adirect interference by food with absorption of the drug, and to thekinetics of release of the drug from the tablet. In the case of the SRtablets of EXAMPLE 3, we infer from in vitro studies that the rate ofrelease of acamprosate from the tablet is the same in the fed state(where most of the drug is released into gastric juice approximatepH=1.0) and in the fasting state (where most of the drug is releasedinto the jejunum and ileum at approximate pH=4.5). Remarkably the threefactors that influence the PK of acamprosate from SNC-102 producefed-fasting equivalence (of AUC and C_(max)). This truly remarkable,unexpected, and prospectively unpredictable finding was produced by thecomposition of matter described above utilizing a carbomer (Carbopol974P) as the principal excipient, and it can be expected to bereplicated by a sustained release tablet with somewhat differentchemical composition, provided that: (1) The pill is sufficiently large(e.g., with at least one dimension exceeding 10 mm) that it will remainin the stomach for four hours or more if taken in the fed state; (2) Thepill maintains its physical integrity in solution at either pH=1.0 orpH=4.5 for 12 hours or more ;(3) The pill releases acamprosate in vitrowith a similar time-concentration curve to the formulation described inEXAMPLE 3; and (4) the pill has essentially the same time-concentrationcurve at pH=1.0 and pH=4.5 For example, a pill utilizing Carbopol 971Pas a principal excipient was shown to have these properties in vitro.Similar tablets utilizing these or other carbomers with various othersecondary excipients have similar in vitro and in vivo properties, assustained-release tablets made with various carbomer excipients havebeen shown to maintain their integrity in both highly acidic and lessacidic solutions, and to release their active ingredient by diffusion.

Procedure of a Gamma Scintigraphy Study in Healthy Male Volunteers toEvaluate Gastric Retention of Samarium-153 Radiolabeled800 mgSustained-Release Acamprosate Tablets under Fasted and Fed Conditions

The radionuclide used for this experiment was ¹⁵³l Sm with a gamma rayenergy of 103 KeV and a half-life of 46 hours. Non-radioactive ¹⁵²SmSamarium oxide in the amount of 3 milligrams was incorporated into each800 mg SR acamprosate tablet. This was accomplished by manufacturingsustained-release acamprosate tablets containing3 mg of anon-radioactive isotope of Samarium (¹⁵²Sm) and irradiating them at theMURR nuclear reactor (Columbia, Mo.) to create ¹⁵³Sm. This was doneaccording to directions supplied by Scintipharma.

The irradiation time was selected to yield about 70 microcuries of the¹⁵³Sm at the time of the scintigraphy experiment.

Subjects 001-006 were each administered dose forms at an appointed timewhich was designated as time zero (0.0).

Serial gamma scintigraphy images were acquired at 15 minute intervalsover 10 hours elapsed time followed by an additional image acquisitionat 12, 14 and 24 hours as needed to complete the study. Each 15 minuteacquisition interval consisted of 3 one-minute data collections. Theimage collection times permitted the identification of the location ofthe radiolabeled dose form in the gastrointestinal tract at therespective time point to provide the time course for the passage of thetablet from one GI location to another.

For example, subject 001 in the fed condition retained the tablet in thestomach throughout the acquisition period of 16.5 hours, whereas thesame subject, in the fasted state, emptied the tablet from the stomachat approximately 0.75 hours the duodenum, after which the tablet rapidlypassed into the jejunum. The tablet remained in the jejunum until 2.75hours when it moved into the ileum for about one hour, leaving at 4.5hours into the ascending colon. After entering the transverse colon andresiding there for 3 hours it moved into the descending colon where itwas visible until 9.5 hours.

FIGS. 8 and 9 show the images of a tablet in the GI tract of subject001. It can be seen that the tablet substantially retained its shape anddimensions in the GI tract in both fasted and fed states.

The GI tract residence time of subjects 001 to 006 is summarized inTABLE 22 below. The average retention times are shown in Table 23.

TABLE 22 Passage of 800 Mg SR Acamprosate Tablets Through TheGastrointestinal Tract of Healthy Male Volunteers in The Fed and FastedStates as Determined by Gamma Scintigraphy Residence Time (hours) forEach Subject Location 001 002 003 004 005 006 Fed stomach 16.5 16.5 16.516.5 4.5 16.5 State jejunium NA NA NA NA NA NA ileum NA NA NA NA 3 NAascending colon NA NA NA NA 5.5 NA Fasted stomach 0.75 0.25 2.25 2.250.75 0.25 State jejunum 2 1 1.25 2.25 1 1 ileum 0.75 3.25 1 1 2.75 1ascending colon 1 1 3 9.5 8.5 NA transverse colon 3 1 1 1 11 1.25descending colon 1 1 NA NA NA 2

TABLE 23 Average Tablet Retention Time (hours) in Each GI Region GIRegion Fasted Fed Stomach 1.1 14.4 Jejunum 1.4 0 Ileum 1.6 3 AscendingColon 3.8 5.5 Transverse Colon 3 0 Descending Colon .7 0

The herein described subject matter sometimes illustrates differentmethods, compositions and/or components contained within, or combinedwith, different other methods, compositions and/or components. It is tobe understood that the various described methods, compositions,components and combinations of the same are merely provided asnon-limiting examples, and that in fact many others can be implementedwhich achieve the same purposes and/or functionality. Additionalnon-limiting examples polymers that can be utilized with theformulations and compositions described herein are found inPHARMACEUTICAL POLYMERS in MARTIN′S PHYSICAL PHARMACY AND PHARMACEUTICALSCIENCES, Sixth Edition 2010, by Patrick J. Sinko and published byWolters Kluwer, ISBN: 9780781797665, at Chapter 20, pp 492-515;electronically available via hypertext transfer protocol (http) atdownloads.1ww.comlwolterskluwer_vitalstream_com/sample-content/9780781797665_Sinko/samples/Chapter_20.pdf,which is incorporated herein by reference in its entirety.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at lease the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the embodiments of the technology.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present embodimentsare not entitled to antedate such publication by virtue of priorinvention. Further, the dates of publication provided may be differentfrom the actual publication dates, which may need to be independentlyconfirmed. The subject matter disclosed in the publications, includingany methods, compositions, excipients (including ranges and dosages ofthe same), etc., are incorporated herein by reference in theirentireties.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. Also, while various aspects and embodiments havebeen disclosed herein, other aspects and embodiments will be apparent tothose skilled in the art. The various aspects and embodiments disclosedherein are for purposes of illustration and are not intended to belimiting, with the true scope and spirit being indicated by thefollowing claims.

1-66. (canceled)
 67. A tablet composition comprising: a polymer matrixcomprised of at least one polymer, wherein the at least one polymercomprises a carbomer; a dose of prazosin dispersed within the polymermatrix, the dose being within a range of about 1.0 mg to about 15 mg;and a dose of acamprosate dispersed within the polymer matrix, wherein:the dose of acamprosate is within a range of about 400 mg to about 1500mg; or the acamprosate is present at a level that is about 20% to about90% of the total weight of the composition; and optionally at least onepharmaceutically acceptable excipient.
 68. The tablet composition ofclaim 67, wherein the carbomer comprises a carbomer selected from thegroup consisting of carbomer homopolymer type A and carbomer homopolymertype B.
 69. The tablet composition of claim 67, wherein the carbomer ispresent at a level that is from about 1% to about 25% of the totalweight of the composition.
 70. The tablet composition of claim 67,wherein the tablet composition has a longest dimension within a range of10-30 mm.
 71. The tablet composition of claim 67, wherein the longestdimension of the tablet composition does not change more than 20% whenmaintained for a period of at least 4-12 hours at a pH within a range ofpH 1.0 to pH 4.5, inclusive.
 72. The tablet composition of claim 67,wherein the tablet composition substantially retains its shape anddimensions in a subject's GI tract after administration to the subject,whether in the fed state or in the fasted state.
 73. The tabletcomposition of claim 67, wherein the acamprosate is present in apharmaceutically acceptable salt form.
 74. The tablet composition ofclaim 67, wherein the tablet composition is characterized in that, whenthe tablet composition is placed in either acetate solution (pH 4.5) orHCl solution (pH 1.0) in vitro, it releases acamprosate at a rate thatis approximately linear with the square root of time and remainscomparable.
 75. The tablet composition of claim 67, wherein the polymermatrix comprises 60 mg of carbomer homopolymer type B, and the dose ofacamprosate is 800 mg.
 76. A method comprising a step of administeringto a subject suffering from or susceptible to an anxiety disorder, PTSD,or panic disorder, a combination of prazosin therapy and acamprosatetherapy.
 77. The method of claim 76, comprising administering the tabletcomposition of claim
 67. 78. The method of claim 76, wherein the subjectis suffering from or susceptible to PTSD.
 79. The method of claim 76,wherein the combination is administered independent of the subject's fedvs fasted state.
 80. A tablet composition comprising: a dose ofacamprosate, that is (i) less than 1 g; and (ii) distributed within apolymer matrix that comprises a carbomer homopolymer type A; andoptionally at least one pharmaceutically acceptable excipient.
 81. Thetablet composition of claim 80, wherein the carbomer is present at alevel that is from about 1% to about 25% of the total weight of thecomposition.
 82. The tablet composition of claim 80, wherein the tabletcomposition substantially retains its shape and dimensions in asubject's GI tract after administration to the subject, whether in thefed state or in the fasted state.
 83. The tablet composition of claim80, wherein the acamprosate is present in a pharmaceutically acceptablesalt form.
 84. The tablet composition of claim 80, wherein the tabletcomposition is characterized in that, when the tablet composition isplaced in either acetate solution (pH 4.5) or HCl solution (pH 1.0) invitro, it releases acamprosate at a rate that is approximately linearwith the square root of time and remains comparable.
 85. The tabletcomposition of claim 80, wherein the polymer matrix comprises 60 mg ofcarbomer homopolymer type A, and the dose of acamprosate is 800 mg. 86.The tablet composition of claim 80, wherein the polymer matrix comprises80 mg of carbomer homopolymer type A, and the dose of acamprosate is 800mg.